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2.
EBioMedicine ; 71: 103558, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34521054

RESUMO

BACKGROUND: Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. METHODS: ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. FINDINGS: ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. INTERPRETATION: These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. FUNDING: This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.

5.
Mol Cancer ; 20(1): 98, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325714

RESUMO

BACKGROUND: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. METHODS: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. RESULTS: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKß-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. CONCLUSION: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

6.
Cancer Res ; 81(14): 3835-3848, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049973

RESUMO

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

7.
Cancer Res ; 81(13): 3525-3538, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33975879

RESUMO

Balancing mRNA nuclear export kinetics with its nuclear decay is critical for mRNA homeostasis control. How this equilibrium is aberrantly disrupted in esophageal cancer to acquire cancer stem cell properties remains unclear. Here we find that the RNA-binding protein interleukin enhancer binding factor 2 (ILF2) is robustly upregulated by nicotine, a major chemical component of tobacco smoke, via activation of JAK2/STAT3 signaling and significantly correlates with poor prognosis in heavy-smoking patients with esophageal cancer. ILF2 bound the THO complex protein THOC4 as a regulatory cofactor to induce selective interactions with pluripotency transcription factor mRNAs to promote their assembly into export-competent messenger ribonucleoprotein complexes. ILF2 facilitated nuclear mRNA export and inhibited hMTR4-mediated exosomal degradation to promote stabilization and expression of SOX2, NANOG, and SALL4, resulting in enhanced stemness and tumor-initiating capacity of esophageal cancer cells. Importantly, inducible depletion of ILF2 significantly increased the therapeutic efficiency of cisplatin and abrogated nicotine-induced chemoresistance in vitro and in vivo. These findings reveal a novel role of ILF2 in nuclear mRNA export and maintenance of cancer stem cells and open new avenues to overcome smoking-mediated chemoresistance in esophageal cancer. SIGNIFICANCE: This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer.

8.
J Exp Clin Cancer Res ; 40(1): 56, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541412

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration. METHODS: ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo. RESULTS: ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3ß)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC. CONCLUSIONS: These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC.

9.
J Hematol Oncol ; 14(1): 6, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407765

RESUMO

BACKGROUND: HOMER family scaffolding proteins (HOMER1-3) play critical roles in the development and progression of human disease by regulating the assembly of signal transduction complexes in response to extrinsic stimuli. However, the role of HOMER protein in breast cancer remains unclear. METHODS: HOMER3 expression was examined by immunohistochemistry in breast cancer patient specimens, and its significance in prognosis was assessed by Kaplan-Meier survival analysis. The effects of HOMER3 in growth factor-induced ß-Catenin activation were analyzed by assays such as TOP/FOP flash reporter, tyrosine phosphorylation assay and reciprocal immunoprecipitation (IP) assay. Role of HOMER3 in breast cancer metastasis was determined by cell function assays and mice tumor models. RESULTS: Herein, we find that, among the three HOMER proteins, HOMER3 is selectively overexpressed in the most aggressive triple negative breast cancer (TNBC) subtype, and significantly correlates with earlier tumor metastasis and shorter patient survival. Mechanismly, HOMER3 interacts with both c-Src and ß-Catenin, thus providing a scaffolding platform to facilitate c-Src-induced ß-Catenin tyrosine phosphorylation under growth factor stimulation. HOMER3 promotes ß-Catenin nuclear translocation and activation, and this axis is clinically relevant. HOMER3 promotes and is essential for EGF-induced aggressiveness and metastasis of TNBC cells both in vitro and in vivo. CONCLUSION: These findings identify a novel role of HOMER3 in the transduction of growth factor-mediated ß-Catenin activation and suggest that HOMER3 might be a targetable vulnerability of TNBC.


Assuntos
Proteínas de Arcabouço Homer/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias de Mama Triplo Negativas/patologia , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Neoplasias de Mama Triplo Negativas/metabolismo , Tirosina/metabolismo
10.
Biochem Biophys Res Commun ; 530(1): 87-94, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32828320

RESUMO

Lymph node metastasis (LNM) is a critical cause for disease progression and treatment failure in cervical cancer. However, the mechanism underlying cervical cancer LNM remains unclear. In this study, HN1 was found to be dramatically upregulated in cervical cancer and patients with higher HN1 expression are more likely to exhibit a higher rate of LNM and lower survival rate. Univariate and multivariate Cox-regression analyses showed that HN1 is an independent prognostic factor in cervical cancer. Meanwhile, HN1 promotes lymphangiogenesis of cervical cancer in vitro. The in vivo experiment also indicates that HN1 enhances LNM in cervical cancer. Furthermore, we also found that HN1 activated the NF-κB signaling pathway to enhance the expression of downstream genes. Taken together, our study suggests that HN1 plays a crucial role in promoting LNM and acts as a prognostic biomarker in cervical cancer.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Linfangiogênese , Metástase Linfática/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/patologia , Animais , Proteínas de Ciclo Celular/análise , Linhagem Celular Tumoral , Feminino , Células HeLa , Humanos , Metástase Linfática/diagnóstico , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/análise , Prognóstico , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/metabolismo
11.
Cell Death Dis ; 11(7): 547, 2020 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-32683421

RESUMO

HER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Receptor ErbB-2/metabolismo , Fator de Transcrição STAT3/metabolismo , Trastuzumab/uso terapêutico , Quinases da Família src/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
12.
Oncogene ; 39(18): 3710-3725, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157210

RESUMO

Radioresistance becomes the major obstacle to reduce tumor recurrence and improve prognosis in the treatment of esophageal squamous cell carcinoma (ESCC). Thus new strategies for radioresistant ESCC are urgently needed. Herein, we reported that tribbles pseudokinase 3 (TRIB3) serves as a key regulator of radioresistance in ESCC. TRIB3 is overexpressed in ESCC tissues and cell lines. High expression of TRIB3 significantly correlates with poor radiotherapy response and prognosis in ESCC patients. Upregulation of TRIB3 in ESCC cells conferred radioresistance in vitro and in vivo by interacting with TAZ thus impeding ß-TrCP-mediated TAZ ubiquitination and degradation. Conversely, silencing TRIB3 sensitized ESCC cells to ionizing radiation. More importantly, TRIB3 was significantly correlated with TAZ activation in ESCC biopsies, and patients with high expression of both TRIB3 and TAZ suffered the worst radiotherapy response and survival. Our study uncovers the critical mechanism of ESCC resistance to radiotherapy, and provides a new pharmacological opportunity for developing a mechanism-based strategy to eliminate radioresistant ESCC in clinical practice.


Assuntos
Proteínas de Ciclo Celular/genética , Carcinoma de Células Escamosas do Esôfago/radioterapia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tolerância a Radiação/genética , Proteínas Repressoras/genética , Transativadores/genética , Animais , Intervalo Livre de Doença , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Células HEK293 , Xenoenxertos , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Ligação Proteica/genética , Proteínas Serina-Treonina Quinases/genética , Proteólise/efeitos da radiação , Radiossensibilizantes/farmacologia , Transdução de Sinais/genética , Ubiquitinação/efeitos da radiação
13.
Oncogene ; 39(12): 2568-2582, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31988454

RESUMO

Circulating tumor cells (CTC) disseminating is an important cause of distant metastasis. However, the mechanism involved in increasing the numbers of CTCs in breast cancer is unclear. Herein, Zinc finger protein 367 (ZNF367) was identified as a potential prometastatic gene in an integrative breast cancer datasets. ZNF367 was upregulated in breast cancer tissues and cell lines, and significantly correlated with poorer metastasis-free and overall survivals in patients. ZNF367 promoted tumor metastasis accompanied with increase of CTC numbers. Mechanistically, ZNF367 interacted with chromatin remodeling protein BRG1 and transcriptionally activated CIT and TP53BP2, leading to the inhibition of the Hippo pathway and activation of YAP1, which gave rise to the resistance of anoikis and increased CTCs in the blood circulation. More importantly, administration of a YAP1 inhibitor Verteporfin resensitized ZNF367-overexpressing breast cancer cells to anoikis and abrogated metastasis. Our findings addressed the importance of ZNF367 in breast cancer as a prognostic biomarker and offered a potential therapeutic strategy for the treatment of a subset of metastatic breast cancer with ZNF367 overexpression.


Assuntos
Neoplasias da Mama/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Metástase Neoplásica , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Anoikis , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , DNA Helicases/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/secundário , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/metabolismo , Prognóstico , Taxa de Sobrevida , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
14.
EMBO Mol Med ; 11(12): e10638, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31657150

RESUMO

Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor-alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt-like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre-tamoxifen-treated and relapsed tamoxifen-resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen-independent growth and tamoxifen resistance in ERα-positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen-resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor-mediated SALL2 restoration resensitized tamoxifen-resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co-therapy with tamoxifen and DNMT inhibitor.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Tamoxifeno/farmacologia , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Epigenômica/métodos , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Regiões Promotoras Genéticas/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
15.
Nat Commun ; 10(1): 3761, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434880

RESUMO

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of ß-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the ß-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for ß-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.


Assuntos
Dano ao DNA/fisiologia , Glutationa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , beta Catenina/metabolismo , Células A549 , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Cromatina , Di-Hidropiridinas/farmacologia , Feminino , Glutationa/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional
16.
EBioMedicine ; 43: 238-252, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31047858

RESUMO

BACKGROUND: Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2-8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC). METHODS: The deletion frequency and expression of NKX2-8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2-8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2-8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays. FINDINGS: NKX2-8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2-8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2-8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2-8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC. INTERPRETATION: Our results demonstrate that NKX2-8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2-8-deleted EOC. FUND: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.


Assuntos
Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Ácidos Graxos/metabolismo , Proteínas de Homeodomínio/genética , Deleção de Sequência , Fatores de Transcrição/genética , Animais , Biomarcadores , Carcinoma Epitelial do Ovário/mortalidade , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Camundongos , Modelos Biológicos , Oxirredução , Prognóstico , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Microambiente Tumoral
17.
Oncogene ; 38(27): 5516-5529, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30936461

RESUMO

The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/ß-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/ß-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of ß-catenin. AKIP1 interacted with and sustained ß-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC). Moreover, AKIP1 enhanced the protein kinase A catalytic subunit (PKAc)-mediated phosphorylation of ß-catenin, leading to recruitment of cyclic AMP response element-binding protein (CBP) and activation of ß-catenin downstream transcription. Increased AKIP1 expression was observed in HCC clinical samples and correlated with early recurrence and poor prognosis of HCC. AKIP1 promoted invasion and colony outgrowth in vitro and increased intrahepatic and lung metastasis in vivo. Treatment with a CBP inhibitor ICG-001 effectively inhibited the metastatic progression of HCC tumors that had elevated AKIP1 in both cell line and patient-derived xenograft mouse models. Our findings not only establish AKIP1 as a novel regulator of Wnt/ß-catenin signaling as well as HCC early recurrence but also highlight targeting the AKIP1/ß-catenin/CBP axis as attractive therapies for combating HCC metastatic relapse.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Nucleares/metabolismo , Via de Sinalização Wnt , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia , Fosforilação , Transcrição Genética
18.
Int J Cancer ; 145(7): 1921-1934, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30895619

RESUMO

The primary challenge facing treatment of epithelial ovarian cancer (EOC) is the high frequency of chemoresistance, which severely impairs the quality of life and survival of patients with EOC. Our study aims to investigate the mechanisms by which upregulation of NR2F6 induces chemoresistance in EOC. The biological roles of NR2F6 in EOC chemoresistance were explored in vitro by Sphere, MTT and AnnexinV/PI assay, and in vivo using an ovarian cancer orthotopic transplantation model. Bioinformatics analysis, luciferase assay, CHIP and IP assays were performed to identify the mechanisms by which NR2F6 promotes chemoresistance in EOC. The expression of NR2F6 was significantly upregulated in chemoresistant EOC tissue, and NR2F6 expression was correlated with poorer overall survival. Moreover, overexpression of NR2F6 promotes the EOC cancer stem cell phenotype; conversely, knockdown of NR2F6 represses the EOC cancer stem cell phenotype and sensitizes EOC to cisplatin in vitro and in vivo. Our results further demonstrate that NR2F6 sustains activated Notch3 signaling, resulting in chemoresistance in EOC cells. Notably, NR2F6 acts as an informative biomarker to identify the population of EOC patients who are likely to experience a favorable objective response to gamma-secretase inhibitors (GSI), which inhibit Notch signaling. Therefore, concurrent inhibition of NR2F6 and treatment with GSI and cisplatin-based chemotherapy may be a novel therapeutic approach for NR2F6-overexpressing EOC. In summary, we have, for the first time, identified an important role for NR2F6 in EOC cisplatin resistance. Our study suggests that GSI may serve as a potential targeted treatment for patients with NR2F6-overexpressing EOC.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Animais , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Cisplatino , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Receptor Notch3/metabolismo , Análise de Sobrevida , Regulação para Cima
19.
J Exp Clin Cancer Res ; 38(1): 33, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678687

RESUMO

BACKGROUND: The primary obstacle to treat cervical cancer is its high prevalence of metastasis, which severely affects patients' quality of life and survival time. Nucleolar and spindle associated protein 1 (NUSAP1) has been implicated in the development, progression, and metastasis in several types of cancer. However, its oncogenic role in cervical cancer remains unclear. METHODS: Western blot assay and immunohistochemistry were used to determine the expression of NUSAP1 in 21 clinical fresh Cervical cancer tissues and 233 clinicopathologically characterized cervical cancer specimens. The biological roles of NUSAP1 in the metastasis of cervical cancer were investigated both in vitro by EMT, Side population analysis and Transwell assays and so on, and in vivo using a mouse 4w model of hematogenous metastasis and lymph node metastasis. Bioinformatics analysis, luciferase reporter analysis, immunoprecipitation and immunoblotting of nuclear and cytoplasmic cellular fractions were applied to discern and examine the relationshipbetween NUSAP1 and its potential targets. RESULTS: The results demonstrated that NUSAP1 was upregulated in cervical cancer cells and tissues, correlated positively with metastasis and poor clinical outcome of patients. High expression of NUSAP1 promoted metastasis by enhancing cancer stem cell (CSC) traits and epithelial-mesenchyme transition (EMT) progression, while silencing of NUSAP1 reduced CSC traits and EMT progression. Mechanistically, upregulation of NUSAP1 induced SUMOylation of TCF4 via interacting with SUMO E3 ligase Ran-binding protein 2 (RanBP2) and hyperactivated Wnt/ß-catenin signaling in cervical cancer cells. Additionally, NUSAP1-induced cervical cancer cells metastasis and the cancer stem cell phenotype were abrogated with the Wnt/ß-catenin signaling inhibitor XAV-939 treatment. Importantly, co-therapy of conventional treatment and XAV-939 will provide a novel and effective treatment for NUSAP1-ovexpressed cervical cancer patients. CONCLUSIONS: Our results demonstrate thatNUSAP1 upregulation contributes to metastasis of cervical cancer by promoting CSC properties and EMT via Wnt/ß-catenin signaling and XAV-939 might serve as a potential tailored therapeutic option for patients with NUSAP1-ovexpressed cervical cancer.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Associadas aos Microtúbulos/genética , Prognóstico , Neoplasias do Colo do Útero/genética , Adulto , Carcinogênese/genética , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/efeitos dos fármacos
20.
Clin Cancer Res ; 25(3): 1022-1035, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279231

RESUMO

PURPOSE: The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/ß-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/ß-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. RESULTS: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited ß-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/ß-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. CONCLUSIONS: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.


Assuntos
Carcinoma Epitelial do Ovário/genética , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , MicroRNAs/genética , Fragmentos de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Sialoglicoproteínas/genética , Transativadores/genética , beta Catenina/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pirimidinonas/administração & dosagem , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transativadores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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