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MicroRNA-572/hMOF/Sirt6 regulates the progression of ovarian cancer.

ABSTRACT: Human males absent on the first (hMOF) is a histone acetyltransferase (HAT) and is involved in the pathogenesis of various cancers. This article aimed to reveal the potential mechanism of the miR-572/hMOF/Sirt6 axis in ovarian cancer (OC). In this study, we found that the mRNA and protein levels of hMOF and Sirt6 were abnormally down-regulated in OC tissues and cells. Further study indicated that the overexpression of hMOF increased the level of H4 histone acetylation in the Sirt6 promoter region and enhanced the ability of hMOF to bind to the Sirt6 promoter in OC cells, and repressed the proliferation of SKOV3 cells and promoted the apoptosis of SKOV3 cells via up-regulating Sirt6. Moreover, it was found that miR-572 negatively regulated hMOF luciferase activity. After the transfection of miR-572 inhibitor into SKOV3 cells, the cell proliferation was significantly repressed, while this repression was reversed after the transfection of shRNA-hMOF. Besides, the overexpression of hMOF could significantly inhibit the growth of tumors. Overall, our findings uncovered a novel regulatory pattern of hMOF in OC progression and provided new insights for relieving OC.

SUBMITTER: Cai M

PROVIDER: S-EPMC7553532 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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MicroRNA-572/hMOF/Sirt6 regulates the progression of ovarian cancer.

Cai Mingbo M Hu Zhenhua Z Han Liping L Guo Ruixia R

Cell cycle (Georgetown, Tex.) 20200823 19

Human males absent on the first (hMOF) is a histone acetyltransferase (HAT) and is involved in the pathogenesis of various cancers. This article aimed to reveal the potential mechanism of the miR-572/hMOF/Sirt6 axis in ovarian cancer (OC). In this study, we found that the mRNA and protein levels of hMOF and Sirt6 were abnormally down-regulated in OC tissues and cells. Further study indicated that the overexpression of hMOF increased the level of H4 histone acetylation in the Sirt6 promoter regio ...[more]

PMID: 33026281

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Project description:Histone acetyltransferase human males absent on the first (hMOF) is a member of MYST family which participates in posttranslational chromatin modification by controlling the acetylation level of histone H4K16. Abnormal activity of hMOF occurs in multiple cancers and biological alteration of hMOF expression can affect diverse cellular functions including cell proliferation, cell cycle progression and embryonic stem cells (ESCs) self-renewal. The relationship between hMOF and cisplatin resistance was investigated in The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) database. Lentiviral-mediated hMOF-overexpressed cells or hMOF-knockdown cells were established to investigate its role on cisplatin-based chemotherapy resistance in vitro ovarian cancer cells and animal models. Furthermore, a whole transcriptome analysis with RNA sequencing was used to explore the underlying molecular mechanism of hMOF affecting cisplatin-resistance in ovarian cancer. The data from TCGA analysis and IHC identification demonstrated that hMOF expression was closely associated with cisplatin-resistance in ovarian cancer. The expression of hMOF and cell stemness characteristics increased significantly in cisplatin-resistant OVCAR3/DDP cells. In the low hMOF expressing ovarian cancer OVCAR3 cells, overexpression of hMOF improved the stemness characteristics, inhibited cisplatin-induced apoptosis and mitochondrial membrane potential impairment, as well as reduced the sensitivity of OVCAR3 cells to cisplatin treatment. Moreover, overexpression of hMOF diminished tumor sensitivity to cisplatin in a mouse xenograft tumor model, accompanied by decrease in the proportion of cisplatin-induced apoptosis and alteration of mitochondrial apoptosis proteins. In addition, opposite phenotype and protein alterations were observed when knockdown of hMOF in the high hMOF expressing ovarian cancer A2780 cells. Transcriptomic profiling analysis and biological experimental verification orientated that MDM2-p53 apoptosis pathway was related to hMOF-modulated cisplatin resistance of OVCAR3 cells. Furthermore, hMOF reduced cisplatin-induced p53 accumulation by stabilizing MDM2 expression. Mechanistically, the increased stability of MDM2 was due to the inhibition of ubiquitinated degradation, which resulted by increased of MDM2 acetylation levels by its direct interaction with hMOF. Finally, genetic inhibition MDM2 could reverse hMOF-mediated cisplatin resistance in OVCAR3 cells with up-regulated hMOF expression. Meanwhile, treatment with adenovirus expressing shRNA of hMOF improved OVCAR3/DDP cell xenograft sensitivity to cisplatin in mouse. Collectively, the results of the study confirm that MDM2 as a novel non-histone substrate of hMOF, participates in promoting hMOF-modulated cisplatin chemoresistance in ovarian cancer cells. hMOF/MDM2 axis might be a potential target for the treatment of chemotherapy-resistant ovarian cancer.

Project description:BackgroundOvarian cancer (OC) has the highest mortality rate among all gynecological malignancies. A hypoxic microenvironment is a common feature of solid tumors, including ovarian cancer, and an important driving factor of tumor cell survival and chemo- and radiotherapy resistance. Previous research identified the hypoxia-associated gene angiopoietin-like 4 (ANGPTL4) as both a pro-angiogenic and pro-metastatic factor in tumors. Hence, this work aimed to further elucidate the contribution of ANGPTL4 to OC progression.MethodsThe expression of hypoxia-associated ANGPTL4 in human ovarian cancer was examined by bioinformatics analysis of TCGA and GEO datasets. The CIBERSORT tool was used to analyze the distribution of tumor-infiltrating immune cells in ovarian cancer cases in TCGA. The effect of ANGPTL4 silencing and overexpression on the proliferation and migration of OVCAR3 and A2780 OC cells was studied in vitro, using CCK-8, colony formation, and Transwell assays, and in vivo, through subcutaneous tumorigenesis assays in nude mice. GO enrichment analysis and WGCNA were performed to explore biological processes and genetic networks associated with ANGPTL4. The results obtained were corroborated in OC cells in vitro by western blotting.ResultsScreening of hypoxia-associated genes in OC-related TCGA and GEO datasets revealed a significant negative association between ANGPTL4 expression and patient survival. Based on CIBERSORT analysis, differential representation of 14 distinct tumor-infiltrating immune cell types was detected between low- and high-risk patient groups. Silencing of ANGPTL4 inhibited OVCAR3 and A2780 cell proliferation and migration in vitro and reduced the growth rate of xenografted OVCAR3 cells in vivo. Based on results from WGCNA and previous studies, western blot assays in cultured OC cells demonstrated that ANGPTL4 activates the Extracellular signal-related kinases 1 and 2 (ERK1/2) pathway and this results in upregulation of c-Myc, Cyclin D1, and MMP2 expression. Suggesting that the above mechanism mediates the pro-oncogenic actions of ANGPTL4T in OC, the pro-survival effects of ANGPTL4 were largely abolished upon inhibition of ERK1/2 signaling with PD98059.ConclusionsOur work suggests that the hypoxia-associated gene ANGPTL4 stimulates OC progression through activation of the ERK1/2 pathway. These findings may offer a new prospect for targeted therapies for the treatment of OC.

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MicroRNA-572/hMOF/Sirt6 regulates the progression of ovarian cancer.

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MicroRNA-572/hMOF/Sirt6 regulates the progression of ovarian cancer.

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