Hepatocellular carcinoma (HCC), with its ineffective therapeutic options and poor prognosis, represents a global threat. In the present study, we show that RAD52 motif 1 (RDM1), a key regulator of DNA double-strand break repair and recombination, is downregulated in HCC tissues and suppresses tumor growth. In clinical HCC samples, low expression of RDM1 correlates with larger tumor size, poor tumor differentiation, and unfavorable survival. In vitro and in vivo data demonstrate that knockdown of RDM1 increases HCC cell proliferation, colony formation, and cell population at G2/M phase, whereas RDM1 overexpression results in the opposite phenotypes. Mechanistically, RDM1 binds to the tumor suppressor p53 and enhances its protein stability. In the presence of p53, RDM1 suppresses the phosphorylation of Raf and ERK. Overexpression of p53 or treatment with ERK inhibitor significantly abolishes cell proliferation induced by the depletion of RDM1. In addition, overexpression of methyltransferase-like 3 markedly induces N6-methyladenosine modification of RDM1 mRNA and represses its expression. Taken together, our study indicates that RDM1 functions as a tumor suppressor and may be a potential prognostic and therapeutic factor for HCC.

中文翻译：

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RDM1的丢失可通过p53和Ras / Raf / ERK途径增强肝癌的进展。

肝细胞癌（HCC）的治疗选择无效且预后不良，这已成为全球性威胁。在本研究中，我们显示RAD52基序1（RDM1），DNA双链断裂修复和重组的关键调节剂，在肝癌组织中下调并抑制了肿瘤的生长。在临床HCC样品中，RDM1的低表达与更大的肿瘤大小，不良的肿瘤分化和不利的生存率相关。体外和体内数据表明，RDM1的敲低会增加HCC细胞增殖，集落形成和G2 / M期的细胞数量，而RDM1的过表达导致相反的表型。从机理上讲，RDM1与肿瘤抑制因子p53结合并增强其蛋白质稳定性。在p53的存在下，RDM1抑制Raf和ERK的磷酸化。p53的过表达或用ERK抑制剂治疗可显着消除RDM1耗尽引起的细胞增殖。此外，甲基转移酶样3的过表达明显诱导RDM1 mRNA的N6-甲基腺苷修饰，并抑制其表达。两者合计，我们的研究表明RDM1发挥抑癌作用，并且可能是HCC的潜在预后和治疗因素。