RESUMEN
Drug resistance is often developed during clinical chemotherapy of ovarian cancers. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) is possibly dependent on tumour context to promote or suppress progression of various tumours. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) was decreased in cisplatin-resistant ovarian cancer cells. The current study identified that both ectopic wild type and nonISGylatable mutant ISG15 expression inhibited CSC-like phenotypes of cisplatin-resistant ovarian cancer cells. Moreover, ectopic ISG15 expression suppressed tumour formation in nude mice. In addition, ISG15 downregulation promoted CSC-like features of cisplatin-sensitive ovarian cancer cells. Furthermore, low ISG15 expression was associated with poor prognosis in patients with ovarian cancer. Transcriptional repressor Krüppel-like factor 12 (KLF12) downregulated ISG15 in cisplatin-resistant cells. Our data indicated that downregulating ISG15 expression, via weakening effect of KLF12, might be considered as new therapeutic strategy to inhibit CSC phenotypes in the treatment of cisplatin-resistant ovarian cancer.
Asunto(s)
Cisplatino/farmacología , Citocinas/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Factores de Transcripción de Tipo Kruppel/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Ováricas/patología , Ubiquitinas/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Movimiento Celular , Proliferación Celular , Citocinas/genética , Femenino , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Células Tumorales Cultivadas , Ubiquitinas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ovarian cancer (OC) is a common gynecological malignant tumor that seriously endangers the health of women worldwide. Tripartite motif containing 29 (TRIM29) is a TRIM family member that is frequently overexpressed in OC. However, the specific role of TRIM29 in OC remains obscure. To investigate the underlying molecular mechanism, a global proteomics analysis identified SET binding protein 1 (SETBP1) as a crucial target of TRIM29. Subsequently, the SETBP1/SET/Protein phosphatase 2 (PP2A) axis was confirmed to be required for the recovery of cancer stem cell (CSC)-like phenotype suppressed by TRIM29 knockdown. Mechanistically, TRIM29 facilitated SETBP1 transcriptional activation via the VEZF1 transcription factor. More importantly, TRIM29 promoted VEZF1 mRNA translation by recruiting RNA binding protein BICC1 to its 3'UTR. The clinical significance was established by the association of TRIM29 and SETBP1 expression with clinicopathological features in OC samples. The SETBP1/SET/PP2A axis driven by TRIM29 via transcription factor VEZF1 is at least one of the primary mechanisms underlying TRIM29 maintenance of the CSC-like characteristics in OC.
Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Chaperonas de Histonas/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/metabolismo , Proteína Fosfatasa 2/metabolismo , Factores de Transcripción/metabolismo , Adulto , Anciano , Animales , Proteínas Portadoras/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Activación Enzimática , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Inmunohistoquímica , Ratones , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Proteínas Nucleares/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/etiología , Regiones Promotoras Genéticas , Transducción de Señal , Factores de Transcripción/genéticaRESUMEN
Ovarian cancer is the most frequent cause of gynecologic malignancies associated death. Primary or acquired cisplatin resistance is frequently occurred during ovarian cancer therapy. Cancer stem cells (CSC) tend to form minimal residual disease after chemotherapy and are implicated in relapse. The ability of cancer cells to reprogram their metabolism has recently been related with maintenance of CSC and resistance to chemotherapies. The current study found that BAG5 expression was decreased in cisplatin-resistant ovarian cancer cells and clinical tissues. Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues. Collectively, the current study identified the implication of Bcl6/BAG5/Rictor-mTORC2 signaling pathway in metabolic reprograming and maintenance of CSC-like features in cisplatin-resistant ovarian cancer cells. Therefore, further studies on the mechanism underlying regulation of metabolic reprogramming and CSC-like characteristics of cisplatin-resistant ovarian cancer cells may contribute to the establishment of novel therapeutic strategy for cisplatin-resistance.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Regulación hacia Abajo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Neoplasias Ováricas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Antineoplásicos/farmacología , Cisplatino/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Transducción de Señal/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Ovarian cancer is the most lethal gynecologic malignant cancer, frequently due to its late diagnosis and high recurrence. Cancer stem cells (CSCs) from different malignancies including ovarian cancer have been linked to chemotherapy resistance and poor prognosis. Therefore, identifying the molecular mechanisms mediating therapy resistance is urgent to finding novel targets for therapy-resistant tumors. Aberrant O-glycosylation ascribed to subtle alteration of GALNT family members during malignant transformation facilitate metastasis in various cancers. The current study demonstrated that BAG3 was upregulated in platin-resistant ovarian cancer tissues and cells, and high BAG3 predicted dismal disease-free survival of patients with ovarian cancer. In addition, the current study showed that BAG3 facilitated CSC-like properties of ovarian cancer cells via regulation of GALTN10. In a term of mechanism, BAG3 epigenetically regulated GALNT10 transactivation via histone H3 lysine 4 (H3K4) presenter WDR5. We demonstrated that WDR5 increased H3K4 trimethylation (H3K4me3) modification at the promoter regions of GALNT10, facilitating recruitment of transcription factor ZBTB2 to the GALNT10 promoter. Collectively, our study uncovers an epigenetic upregulation of GALNT10 by BAG3 via WDR5 to facilitate CSCs of platin-resistant ovarian cancers, providing additional information for further identification of attractive targets with therapeutic significance in platin-resistant ovarian cancer.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Epigénesis Genética/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , N-Acetilgalactosaminiltransferasas/genética , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas Reguladoras de la Apoptosis/metabolismo , Carboplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , N-Acetilgalactosaminiltransferasas/deficiencia , N-Acetilgalactosaminiltransferasas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Células Tumorales Cultivadas , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
TRIM29 is dysregulated in pancreatic cancer and implicated in maintenance of stem-cell-like characters of pancreatic cancer cells. However, the exact mechanisms underlying oncogenic function of TRIM29 in pancreatic cancer cells remain largely unclarified. Using a global screening procedure, the current study found that adenylate kinase 4 (AK4) was profoundly reduced by TRIM29 knockdown. In addition, our data demonstrated that TRIM29 knockdown altered bioenergetics and suppressed proliferation and invasion of pancreatic cancer cells via downregulation of AK4 at the posttranscriptional level. The current study demonstrated that upregulation of microRNA-2355-3p (miR-2355-3p) upregulated AK4 expression via facilitating DDX3X recruitment to the AK4 transcript, and TRIM29 knockdown thereby destabilized the AK4 transcript via miR-2355-3p downregulation. Collectively, our study uncovers posttranscriptional stabilization of the AK4 transcript by miR-2355-3p interaction to facilitate DDX3X recruitment. Regulation of AK4 by TRIM29 via miR-2355-3p thereby provides additional information for further identification of attractive targets for therapy with pancreatic cancer.