MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition

Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Cancer Research (Impact Factor: 9.33). 07/2012; 72(16):4037-46. DOI: 10.1158/0008-5472.CAN-12-0103
Source: PubMed


Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability. The DNA repair protein RAD51 and the trans-lesion synthesis DNA polymerase REV1 are required for resistance to DNA interstrand cross-linking agents such as cisplatin. In this study, we show that overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage. MiR-96 directly targeted the coding region of RAD51 and the 3'-untranslated region of REV1. Overexpression of miR-96 decreased the efficiency of homologous recombination and enhanced sensitivity to the PARP inhibitor AZD2281 in vitro and to cisplatin both in vitro and in vivo. Taken together, our findings indicate that miR-96 regulates DNA repair and chemosensitivity by repressing RAD51 and REV1. As a therapeutic candidate, miR-96 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage.

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Available from: Yemin Wang, May 31, 2015
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    • "The target genes of miR-96 that have been experimentally identified by previous researches included FOXO1 [9] [19], FOXO3a [23], RAD51 [24], REV1 [24], and RECK [21]. However, regulatory components of Wnt/b-catenin pathway have not been identified to be on the list of miR-96 target genes. "
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    ABSTRACT: We found that miR-96 is overexpressed in glioma, and its level inversely correlates with the survival of patients. The reduction in miR-96 abundance suppresses the proliferation and colony formation of glioma cells. The tumorigenicity of U-87 MG cells is reduced by miR-96 silencing. miR-96 contributes to the activation of Wnt/β-catenin pathway in glioma cells. HMG-box transcription factor 1 (HBP-1), a Wnt/β-catenin pathway inhibitor, is suppressed by miR-96. The reactivation of Wnt/β-catenin signaling causes an increase in the proliferation of glioma cells, and a decrease in miR-96 expression. On the other hand, HBP1 silencing promotes miR-96 expression. Collectively, miR-96 contributes to the progression of glioma by enhancing the activation of the Wnt/β-catenin pathway, and the miR-96/HBP1/Wnt/β-catenin regulatory circuitry promotes the proliferation of glioma cells.
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    • "High RAD21 expression was associated with genomic instability and miR-299-5p, a microRNA already involved in breast cancer and in oral squamous cell carcinoma, was predicted to be a RAD21 regulator. Wang et al. [94] demonstrated that the expression of RAD51 and REV1 polymerase, involved in the resistance to DNA interstrand crosslinking agents, was downregulated by miR-96 in several types of cancer cells. MiR-96 was able to directly target the coding region of RAD51 and the 3′UTR of REV1. "
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    ABSTRACT: Cancer is a multistep process characterized by various and different genetic lesions which cause the transformation of normal cells into tumor cells. To preserve the genomic integrity, eukaryotic cells need a complex DNA damage/repair response network of signaling pathways, involving many proteins, able to induce cell cycle arrest, apoptosis, or DNA repair. Chemotherapy and/or radiation therapy are the most commonly used therapeutic approaches to manage cancer and act mainly through the induction of DNA damage. Impairment in the DNA repair proteins, which physiologically protect cells from persistent DNA injury, can affect the efficacy of cancer therapies. Recently, increasing evidence has suggested that microRNAs take actively part in the regulation of the DNA damage/repair network. MicroRNAs are endogenous short noncoding molecules able to regulate gene expression at the post-transcriptional level. Due to their activity, microRNAs play a role in many fundamental physiological and pathological processes. In this review we report and discuss the role of microRNAs in the DNA damage/repair and cancer.
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    • "We and others have previously shown that miR-96 levels are upregulated in PCa [5,7,11] and that it is also highly expressed in several other cancer types, including lymphoma, liver, breast, ovarian, lung, colon, testicular and colorectal cancer [5,12]. miR-96 has been suggested to act as an oncomiR regulating proliferation and DNA repair [13], but also as a tumor suppressor inducing apoptosis in pancreatic cells [14]. In breast cancer, miR-96 promotes cell proliferation through targeting the tumor suppressor gene Forkhead box O transcription factor, FOXO3a, and the cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1 [15]. "
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