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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    • "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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    • "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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