RESUMEN
How deregulation of chromatin modifiers causes malignancies is of general interest. Here, we show that histone H2A T120 is phosphorylated in human cancer cell lines and demonstrate that this phosphorylation is catalyzed by hVRK1. Cyclin D1 was one of ten genes downregulated upon VRK1 knockdown in two different cell lines and showed loss of H2A T120 phosphorylation and increased H2A K119 ubiquitylation of its promoter region, resulting in impaired cell growth. In vitro, H2A T120 phosphorylation and H2A K119 ubiquitylation are mutually inhibitory, suggesting that histone phosphorylation indirectly activates chromatin. Furthermore, expression of a phosphomimetic H2A T120D increased H3 K4 methylation. Finally, both VRK1 and the H2A T120D mutant histone transformed NIH/3T3 cells. These results suggest that histone H2A T120 phosphorylation by hVRK1 causes inappropriate gene expression, including upregulated cyclin D1, which promotes oncogenic transformation.
Asunto(s)
Transformación Celular Neoplásica/genética , Ciclina D1/genética , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/genética , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Cromatina/química , Cromatina/metabolismo , Ciclina D1/metabolismo , Proteínas de Drosophila , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células HeLa , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metilación , Ratones , Oligopéptidos/genética , Oligopéptidos/metabolismo , Fosforilación , Protamina Quinasa/genética , Protamina Quinasa/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Transducción de Señal , Treonina/metabolismo , UbiquitinaciónRESUMEN
Androgen receptor (AR) signaling is essential for prostate cancer progression and acquiring resistance to hormone therapy. However, the molecular pathogenesis through AR activation has not been fully understood. We performed integrative transcriptomic analysis to compare the AR program in a castration-resistant prostate cancer (CRPC) model with that in their parental hormone-sensitive cells. We found that the gene cordon-bleu-like 1 (COBLL1) is highly induced by AR in CRPC model cells. The expression of COBLL1 that possesses an actin-binding domain is up-regulated in clinical prostate cancer tissues and is associated with a poor prognosis for prostate cancer patients. COBLL1 is involved in the cancer cell morphogenesis to a neuron-like cell shape observed in the CRPC model cells, promoting cell growth and migration. Moreover, nuclear COBLL1 interacts with AR to enhance complex formation with CDK1 and facilitates AR phosphorylation for genomic binding in CRPC model cells. Thus, our findings showed the mechanistic relevance of cordon-bleu proteins during the AR-mediated progression to CRPC.
Asunto(s)
Movimiento Celular , Núcleo Celular/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/metabolismo , Factores de Transcripción/metabolismo , Animales , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/patología , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Complejos Multiproteicos/genética , Proteínas de Neoplasias/genética , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Dominios Proteicos , Receptores Androgénicos/genética , Factores de Transcripción/genéticaRESUMEN
Octamer transcription factor 1 (OCT1) is a transcriptional factor reported to be a poor prognostic factor in various cancers. However, the clinical value of OCT1 in breast cancer is not fully understood. In the present study, an immunohistochemical study of OCT1 protein was performed using estrogen receptor (ER)-positive breast cancer tissues from 108 patients. Positive OCT1 immunoreactivity (IR) was associated with the shorter disease-free survival (DFS) of patients (p = 0.019). Knockdown of OCT1 inhibited cell proliferation in MCF-7 breast cancer cells as well as its derivative long-term estrogen-deprived (LTED) cells. On the other hand, the overexpression of OCT1 promoted cell proliferation in MCF-7 cells. Using microarray analysis, we identified the non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH) as a novel OCT1-taget gene in MCF-7 cells. Immunohistochemical analysis showed that NCAPH IR was significantly positively associated with OCT1 IR (p < 0.001) and that positive NCAPH IR was significantly related to the poor DFS rate of patients (p = 0.041). The knockdown of NCAPH inhibited cell proliferation in MCF-7 and LTED cells. These results demonstrate that OCT1 and its target gene NCAPH are poor prognostic factors and potential therapeutic targets for patients with ER-positive breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Proteínas de Ciclo Celular/genética , Proliferación Celular/genética , Proteínas Nucleares/genética , Factor 1 de Transcripción de Unión a Octámeros/genética , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Células MCF-7 , Persona de Mediana Edad , Invasividad Neoplásica/genética , Proteínas Nucleares/metabolismo , Factor 1 de Transcripción de Unión a Octámeros/metabolismo , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptores de Estrógenos/metabolismoRESUMEN
Neuroblastoma (NB) is a childhood malignancy originating from the sympathetic nervous system, and accounts for approximately 15% of all pediatric cancer-related deaths. As the 5-y survival rate of patients with high-risk NB is <50%, novel therapeutic strategies for NB patients are urgently required. Nonaethylene glycol mono('4-iodo-4-biphenyl)ester (9bw) is a polyethylene glycol derivative, synthesized by modifying a compound originally extracted from filamentous bacteria. Although 9bw shows remarkable inhibition of tumor cell growth, the underlying mechanisms remain unclear. Here, we examined the efficacy of 9bw on human NB-derived cells, and investigated the molecular mechanisms underlying the cytotoxic effects of 9bw on these cells. Our results indicated that 9bw induced cell death in NB cells by decreasing the production of ATP. Metabolome analysis and measurement of oxygen consumption indicated that 9bw markedly suppressed oxidative phosphorylation (OXPHOS). Further analyses indicated that 9bw inhibited the activity of mitochondrial respiratory complex I. Moreover, we showed that 9bw inhibited growth of NB in vivo. Based on the results of the present study, 9bw is a good candidate as a novel agent for treatment of NB.
Asunto(s)
Antineoplásicos/farmacología , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Ésteres/farmacología , Neuroblastoma/tratamiento farmacológico , Fosforilación Oxidativa/efectos de los fármacos , Polietilenglicoles/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejo I de Transporte de Electrón/metabolismo , Ésteres/química , Ésteres/uso terapéutico , Femenino , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuroblastoma/patología , Polietilenglicoles/química , Polietilenglicoles/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
TRIM44 has oncogenic roles in various cancers. However, TRIM44 expression and its function in renal cell carcinoma (RCC) are still unknown. Here in this study, we investigated the clinical significance of TRIM44 and its biological function in RCC. TRIM44 overexpression was significantly associated with clinical M stage, histologic type (clear cell) and presence of lymphatic invasion (P = .047, P = .005, and P = .028, respectively). Moreover, TRIM44 overexpression was significantly associated with poor prognosis in terms of cancer-specific survival (P = .019). Gain-of-function and loss-of-function studies using TRIM44 and siTRIM44 transfection showed that TRIM44 promotes cell proliferation and cell migration in two RCC cell lines, Caki1 and 769P. To further investigate the role of TRIM44 in RCC, we performed integrated microarray analysis in Caki1 and 769P cells and explored the data in the Oncomine database. Interestingly, FRK was identified as a promising candidate target gene of TRIM44, which was downregulated in RCC compared with normal renal tissues. We found that cell proliferation was inhibited by TRIM44 knockdown and then recovered by siFRK treatment. Taken together, the present study revealed the association between high expression of TRIM44 and poor prognosis in RCC patients and that TRIM44 promotes cell proliferation by regulating FRK.
Asunto(s)
Carcinoma de Células Renales/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Renales/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pronóstico , Transducción de Señal/fisiologíaRESUMEN
The majority of breast cancers are primarily hormone-sensitive and can be managed by endocrine therapy, although therapy-resistant or hormone-refractory cancers need alternative treatments. Recently, increasing attention is being paid to RNA-binding proteins (RBP) in cancer pathophysiology. The precise role of RBP in breast cancer, however, remains to be clarified. We herein show that an RBP non-POU domain-containing octamer binding (NONO) plays a critical role in the pathophysiology of breast cancers regardless of their hormone dependency. Clinicopathological and immunohistochemical study of 127 breast cancer cases showed that NONO is a significant independent prognostic factor for breast cancer patients. Notably, siRNA-mediated NONO knockdown substantially repressed the proliferation of both hormone-sensitive MCF-7 and hormone-refractory MB-MDA-231 breast cancer cells. Integrative analysis combined with expression microarray and RIP-sequencing (RNA immunoprecipitation-sequencing) showed that NONO post-transcriptionally regulates the expression of cell proliferation-related genes by binding to their mRNAs, as exemplified by S-phase-associated kinase 2 and E2F transcription factor 8. Overall, these results suggest that NONO is a key regulator for breast cancer proliferation through the pre-mRNA splicing of cell proliferation-related genes and could be a potential new diagnostic and therapeutic target for advanced disease.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/genética , Proteínas de Unión al ADN/genética , Procesamiento Postranscripcional del ARN/genética , Proteínas de Unión al ARN/genética , Proteínas Represoras/genética , Proteínas Quinasas Asociadas a Fase-S/genética , Línea Celular Tumoral , Femenino , Regulación de la Expresión Génica/genética , Humanos , Inmunoprecipitación/métodos , Células MCF-7 , ARN Mensajero/genéticaRESUMEN
Amyloid precursor protein (APP) is a representative gene related to Alzheimer's disease (AD). Androgens function by binding to the androgen receptor (AR). Both androgen and RNA-binding protein PSF play a role in the pathology of AD. However, the involvement of AR and PSF in APP regulation in neuron has not been investigated. Here, we explored the regulatory mechanism of APP expression by AR and PSF using neuron-derived cells. We demonstrated that androgen up-regulates the production of APP at the mRNA and protein levels. This induction is enhanced by AR over-expression and inhibited by its silencing. One candidate AR-binding region was identified in the intron region of APP and validated its activity as AR-dependent enhancer by the luciferase assay. Furthermore, the public transcriptome data of brain tissues of mice indicated that APP is regulated by PSF post-transcriptionally. We observed a decreased expression of APP after PSF knockdown and interaction of PSF with the APP transcript. Moreover, we revealed that silencing of PSF inhibited the stability of the APP mRNA. Thus, these results presented a new regulatory mechanism of APP expression by androgen through AR-mediated transcription and PSF at the post-transcriptional level that might be associated with the occurrence of AD.
Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Andrógenos/genética , Andrógenos/metabolismo , Neuronas/metabolismo , Proteínas de Unión al ARN/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Factor de Empalme Asociado a PTB/genética , Unión Proteica , ARN Mensajero/metabolismo , Receptores Androgénicos , Transcriptoma , Regulación hacia ArribaRESUMEN
Developing therapeutic approaches are necessary for treating hormone-refractory prostate cancer. Activation of androgen receptor (AR) and its variants' expression along with the downstream signals are mostly important for disease progression. However, the mechanism for marked increases of AR signals and its expression is still unclear. Here, we revealed that various spliceosome genes are aberrantly induced by RNA-binding protein PSF, leading to enhancement of the splicing activities for AR expression. Our high-speed sequence analyses identified global PSF-binding transcripts. PSF was shown to stabilize and activate key long noncoding RNAs and AR-regulated gene expressions in prostate cancer cells. Interestingly, mRNAs of spliceosome-related genes are putative primary targets of PSF. Their gene expressions are up-regulated by PSF in hormone-refractory prostate cancer. Moreover, PSF coordinated these spliceosome proteins to form a complex to promote AR splicing and expression. Thus, targeting PSF and its related pathways implicates the therapeutic possibility for hormone-refractory prostate cancer.
Asunto(s)
Factor de Empalme Asociado a PTB/biosíntesis , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Largo no Codificante/genética , Receptores Androgénicos/biosíntesis , Empalmosomas/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Factor de Empalme Asociado a PTB/genética , Neoplasias de la Próstata Resistentes a la Castración/terapia , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Receptores Androgénicos/genética , Trasplante HeterólogoRESUMEN
Octamer transcription factor 1 (OCT1) is an androgen receptor (AR)-interacting partner and regulates the expression of target genes in prostate cancer cells. However, the function of OCT1 in castration-resistant prostate cancer (CRPC) is not fully understood. In the present study, we used 22Rv1 cells as AR-positive CRPC model cells to analyze the role of OCT1 in CRPC. We showed that OCT1 knockdown suppressed cell proliferation and migration of 22Rv1 cells. Using microarray analysis, we identified four AR and OCT1-target genes, disks large-associated protein 5 (DLGAP5), kinesin family member 15 (KIF15), non-SMC condensin I complex subunit G (NCAPG), and NDC80 kinetochore complex component (NUF2) in 22Rv1 cells. We observed that knockdown of DLGAP5 and NUF2 suppresses growth and migration of 22Rv1 cells. Furthermore, immunohistochemical analysis showed that positive expression of DLGAP5 in prostate cancer specimens is related to poor cancer-specific survival rates of patients. Notably, enhanced expression of DLGAP5 was observed in CRPC tissues of patients. Thus, our findings suggest that these four genes regulated by the AR/OCT1 complex could have an important role in CRPC progression.
Asunto(s)
Proteínas de Ciclo Celular/genética , Cinesinas/genética , Proteínas de Neoplasias/genética , Factor 1 de Transcripción de Unión a Octámeros/fisiología , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Anciano , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Proteínas del Citoesqueleto , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Masculino , Análisis por Micromatrices , Proteínas Nucleares/genética , Factor 1 de Transcripción de Unión a Octámeros/genética , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Receptores Androgénicos/metabolismo , Tasa de Supervivencia , Regulación hacia ArribaRESUMEN
Tripartite motif 36 (TRIM36) belongs to the TRIM family, most members of which are involved in ubiquitination and degradation of target proteins by functioning as E3 ubiquitin ligases. The function of TRIM36 has not been well documented, therefore, we investigated the clinical significance and function of TRIM36 in human prostate cancer (PC). Multivariate logistic regression analysis showed that TRIM36 immunoreactivity was an independent predictor of cancer-specific survival of PC patients. Gain-of-function study revealed that overexpression of TRIM36 suppressed cell proliferation and migration of LNCaP, 22Rv1, and DU145 cells. Moreover, TRIM36 knockdown using siRNA suppressed apoptosis and promoted cell proliferation and migration in LNCaP and 22Rv1 cells. Furthermore, our microarray analysis revealed that the apoptosis-related pathway was significantly upregulated by TRIM36 overexpression. The TUNEL assay showed that apoptosis promoted by docetaxel treatment was alleviated in siTRIM36-treated LNCaP and 22Rv1 cells. Taken together, these results suggest that high expression of TRIM36 is associated with favorable prognosis and that TRIM36 plays a tumor-suppressive role by inhibiting cell proliferation and migration as well as promoting apoptosis in PC.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Neoplasias de la Próstata/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Clasificación del Tumor , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Supervivencia sin Progresión , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal , Regulación hacia ArribaRESUMEN
Long noncoding RNAs (lncRNA) have been associated with the development of cancer. However, the interplay between lncRNAs and androgen receptor (AR) signaling in prostate cancer is still unclear. Here, we identified lncRNAs induced by androgen in AR-positive prostate cancer cells, where induction was abolished by AR knockdown as well as an anti-androgen, bicalutamide. By combining these data, we identified an androgen-regulated lncRNA, suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells, i.e long-term androgen-deprived (LTAD) cells, than in parental androgen-dependent LNCaP cells. SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10 These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis.
Asunto(s)
Andrógenos/farmacología , Apoptosis/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , ARN Largo no Codificante/biosíntesis , ARN Neoplásico/biosíntesis , Regulación hacia Arriba/efectos de los fármacos , Línea Celular Tumoral , Epigénesis Genética/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Largo no Codificante/genética , ARN Neoplásico/genética , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Regulación hacia Arriba/genéticaRESUMEN
Long non-coding RNAs (lncRNAs) are RNA transcripts larger than 200 nucleotides that do not code for proteins the aberrant expression of which has been documented in various types of cancer, including prostate cancer. Lack of appropriate sensitive and specific biomarkers for prostate cancer has led to overdiagnosis and overtreatment, making lncRNAs promising novel biomarkers as well as therapeutic targets for the disease. The present review attempts to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer, which contribute to carcinogenesis. In particular, we focused on lncRNAs regulated by androgen receptor and expressed in castration-resistant prostate cancer.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Uso Excesivo de los Servicios de Salud , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patologíaRESUMEN
The proliferation of prostate cancer cells is controlled by the androgen receptor (AR) signaling pathway. However, the function of AR target genes has not been fully elucidated. In previous studies, we have identified global AR binding sites and AR target genes in prostate cancer cells. Here, we focused on Claudin 8 (CLDN8), a protein constituting tight junctions in cell membranes. We found one AR binding site in the promoter region and two functional androgen-responsive elements in the sequence. Reporter assay revealed that transcriptional activation of the CLDN8 promoter by androgen is dependent on these androgen-responsive elements. Furthermore, CLDN8 mRNA is induced by androgen time-dependently and the induction is blocked by AR inhibitor, suggesting that AR is involved in the transcriptional activation. In addition, our functional analyses by overexpression and knockdown of CLDN8 mRNA indicate that CLDN8 promotes prostate cancer cell proliferation and migration. Claudin 8 was overexpressed in prostate cancer clinical samples compared to benign tissues. Furthermore, we found that CLDN8 regulates intracellular signal transduction and stabilizes the cytoskeleton. Taken together, these results indicate that CLDN8 functions as an AR downstream signal to facilitate the progression of prostate cancer. Claudin 8 may be a novel molecular target for prostate cancer therapy.
Asunto(s)
Movimiento Celular , Proliferación Celular , Claudinas/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias de la Próstata/patología , Western Blotting , Movimiento Celular/genética , Proliferación Celular/genética , Inmunoprecipitación de Cromatina , Ensayo de Cambio de Movilidad Electroforética , Humanos , Inmunohistoquímica , Masculino , Reacción en Cadena de la Polimerasa , Receptores Androgénicos/metabolismo , Elementos de Respuesta/genética , Activación TranscripcionalRESUMEN
Although long non-coding RNAs (lncRNAs) have been associated with a variety of cancers, the interplay between lncRNAs and androgen receptor signaling in prostate cancer is still unclear. We identified an androgen-dependent lncRNA, POTEF-AS1, whose expression was regulated by androgen receptor in two androgen-dependent cells by using directional RNA sequencing analysis. POTEF-AS1 promoted cell growth, repressed genes related to the Toll-like receptor signaling and apoptosis pathways, and inhibited apoptosis in docetaxel-treated LNCaP cells. These findings suggest that POTEF-AS1 would play a key role in the progression of prostate cancer by repressing Toll-like receptor signaling.
Asunto(s)
Antígenos de Neoplasias/genética , Apoptosis/genética , Supervivencia Celular/genética , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Receptores Androgénicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/genética , Docetaxel , Humanos , Masculino , Neoplasias de la Próstata/patología , Interferencia de ARN , ARN Interferente Pequeño/genética , Transducción de Señal/genética , Taxoides/farmacología , Receptores Toll-Like/antagonistas & inhibidoresRESUMEN
Long-chain acyl-coenzyme A (CoA) synthetase 3 (ACSL3) is an androgen-responsive gene involved in the generation of fatty acyl-CoA esters. ACSL3 is expressed in both androgen-sensitive and castration-resistant prostate cancer (CRPC). However, its role in prostate cancer remains elusive. We overexpressed ACSL3 in androgen-dependent LNCaP cells and examined the downstream effectors of ACSL3. Furthermore, we examined the role of ACSL3 in the androgen metabolism of prostate cancer. ACSL3 overexpression led to upregulation of several genes such as aldo-keto reductase 1C3 (AKR1C3) involved in steroidogenesis, which utilizes adrenal androgen dehydroepiandrosterone sulfate (DHEAS) as substrate, and downregulated androgen-inactivating enzyme UDP-glucuronosyltransferase 2 (UGT2B). Exposure to DHEAS significantly increased testosterone levels and cell proliferative response in ACSL3-overexpressing cells when compared to that in control cells. A public database showed that ACSL3 level was higher in CRPC than in hormone-sensitive prostate cancer. CRPC cells showed an increased expression of ACSL3 and an expression pattern of AKR1C3 and UGT2B similar to ACSL3-overexpressing cells. DHEAS stimulation significantly promoted the proliferation of CRPC cells when compared to that of LNCaP cells. These findings suggest that ACSL3 contributes to the growth of CRPC through intratumoral steroidogenesis (i.e. promoting androgen synthesis from DHEAS and preventing the catabolism of active androgens).
Asunto(s)
Coenzima A Ligasas/genética , Coenzima A Ligasas/metabolismo , Sulfato de Deshidroepiandrosterona/farmacología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Testosterona/metabolismo , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucuronosiltransferasa/metabolismo , Humanos , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Lipogénesis , Masculino , Neoplasias de la Próstata Resistentes a la Castración/genéticaRESUMEN
Tripartite motif 44 (TRIM44) is one of the TRIM family proteins that are involved in ubiquitination and degradation of target proteins by modulating E3 ubiquitin ligases. TRIM44 overexpression has been observed in various cancers. However, its association with testicular germ cell tumor (TGCT) is unknown. We aimed to investigate the clinical significance of TRIM44 and its function in TGCT. High expression of TRIM44 was significantly associated with α feto-protein levels, clinical stage, nonseminomatous germ cell tumor (NSGCT), and cancer-specific survival (P = 0.0009, P = 0.0035, P = 0.0004, and P = 0.0140, respectively). Multivariate analysis showed that positive TRIM44 IR was an independent predictor of cancer-specific mortality (P = 0.046). Gain-of-function study revealed that overexpression of TRIM44 promoted cell proliferation and migration of NTERA2 and NEC8 cells. Knockdown of TRIM44 using siRNA promoted apoptosis and repressed cell proliferation and migration in these cells. Microarray analysis of NTERA2 cells revealed that tumor suppressor genes such as CADM1, CDK19, and PRKACB were upregulated in TRIM44-knockdown cells compared to control cells. In contrast, oncogenic genes including C3AR1, ST3GAL5, and NT5E were downregulated in those cells. These results suggest that high expression of TRIM44 is associated with poor prognosis and that TRIM44 plays significant role in cell proliferation, migration, and anti-apoptosis in TGCT.
Asunto(s)
Apoptosis , Proteínas Portadoras/metabolismo , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patología , Adulto , Apoptosis/genética , Proteínas Portadoras/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Oncogenes/genética , Pronóstico , Proteínas de Motivos TripartitosRESUMEN
High-throughput techniques have identified numerous antisense (AS) transcripts and long non-coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen-responsive long ncRNA, CTBP1-AS, located in the AS region of C-terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1-AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1-AS promotes both hormone-dependent and castration-resistant tumour growth. Mechanistically, CTBP1-AS directly represses CTBP1 expression by recruiting the RNA-binding transcriptional repressor PSF together with histone deacetylases. CTBP1-AS also exhibits global androgen-dependent functions by inhibiting tumour-suppressor genes via the PSF-dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression.
Asunto(s)
Núcleo Celular/metabolismo , Neoplasias de la Próstata/metabolismo , ARN Largo no Codificante/metabolismo , ARN Neoplásico/metabolismo , Anciano , Oxidorreductasas de Alcohol/biosíntesis , Oxidorreductasas de Alcohol/genética , Animales , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/patología , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Factor de Empalme Asociado a PTB , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Largo no Codificante/genética , ARN Neoplásico/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
Hormonal alterations with aging contribute to the pathogenesis of several diseases. Androgens mediate their effects predominantly through binding to the androgen receptor (AR), a member of the ligand-dependent nuclear receptor superfamily. By androgen treatment, AR is recruited to specific genomic loci dependent on tissue specific pioneer factors to regulate target gene expression. Recent studies have revealed the epigenetic modulation by AR-associated histone modifiers and the roles of non-coding RNAs in AR signaling. Androgens are male sex hormone to induce differentiation of the male reproductive system required for the establishment of adult sexual function. As shown by several reports using AR knockout mouse models, androgens also have anabolic functions in several tissues such as bone, muscle and central nervous systems. Notably, AR has a central role in prostate cancer progression. Prostate cancer is the most frequently diagnosed cancer in men. Androgen-deprivation therapy for cancer patients and decline of serum androgen with aging promote several diseases associated with aging and quality of life of older men such as osteoporosis, sarcopenia and dementia. Thus, androgen replacement therapy for treating late onset hypogonadism (LOH) or new epigenetic regulators have the potential to overcome the symptoms caused by the low androgen, although adverse effects for cardiovascular diseases have been reported. Given the increasing longevity and consequent rise of age-related diseases and prostate cancer patients, a more understanding of the AR actions in male health remains a high research priority.
Asunto(s)
Envejecimiento , Andrógenos/uso terapéutico , Enfermedad Crónica/prevención & control , Terapia de Reemplazo de Hormonas , Modelos Biológicos , Neoplasias/prevención & control , Receptores Androgénicos/metabolismo , Andrógenos/efectos adversos , Andrógenos/metabolismo , Animales , Enfermedad Crónica/epidemiología , Demencia/epidemiología , Demencia/metabolismo , Demencia/prevención & control , Epigénesis Genética/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Masculino , Neoplasias/epidemiología , Neoplasias/metabolismo , Osteoporosis/epidemiología , Osteoporosis/metabolismo , Osteoporosis/prevención & control , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/prevención & control , Calidad de Vida , Receptores Androgénicos/química , Receptores Androgénicos/genética , Riesgo , Sarcopenia/epidemiología , Sarcopenia/metabolismo , Sarcopenia/prevención & controlRESUMEN
Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.
Asunto(s)
Adenina/metabolismo , MicroARNs/metabolismo , Neoplasias/genética , ARN Nucleotidiltransferasas/metabolismo , Estabilidad del ARN , Secuencia de Bases , Citosina/metabolismo , Exorribonucleasas/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Células MCF-7 , MicroARNs/química , MicroARNs/genética , Modelos Biológicos , Datos de Secuencia Molecular , Neoplasias/patología , Conformación de Ácido Nucleico , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ribonucleasa III/metabolismoRESUMEN
Aberrant overexpression of ERG induced by the TMPRSS2-ERG gene fusion is likely involved in the development of prostate cancer. Synthetic pyrrole-imidazole (PI) polyamides recognize and attach to the minor groove of DNA with high affinity and specificity. In the present study, we designed a PI polyamide targeting TMPRSS2-ERG translocation breakpoints and assessed its effect on human prostate cancer cells. Our study identified that this PI polyamide repressed the cell and tumor growth of androgen-sensitive LNCaP prostate cancer cells. Targeting of these breakpoint sequences by PI polyamides could be a novel approach for the treatment of prostate cancer.