MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou, 510275, P. R. China.
Key Laboratory of Liver Disease of Guangdong Province, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Cell Death Dis. 2021 Oct 20;12(11):970. doi: 10.1038/s41419-021-04238-x.
Oncogenic c-Myc is a master regulator of G1/S transition. Long non-coding RNAs (lncRNAs) emerge as new regulators of various cell activities. Here, we found that lncRNA SnoRNA Host Gene 17 (SNHG17) was elevated at the early G1-phase of cell cycle. Both gain- and loss-of function studies disclosed that SNHG17 increased c-Myc protein level, accelerated G1/S transition and cell proliferation, and consequently promoted tumor cell growth in vitro and in vivo. Mechanistically, the 1-150-nt of SNHG17 physically interacted with the 1035-1369-aa of leucine rich pentatricopeptide repeat containing (LRPPRC) protein, and disrupting this interaction abrogated the promoting role of SNHG17 in c-Myc expression, G1/S transition, and cell proliferation. The effect of SNHG17 in stimulating cell proliferation was attenuated by silencing c-Myc or LRPPRC. Furthermore, silencing SNHG17 or LRPPRC increased the level of ubiquitylated c-Myc and reduced the stability of c-Myc protein. Analysis of human hepatocellular carcinoma (HCC) tissues revealed that SNHG17, LRPPRC, and c-Myc were significantly upregulated in HCC, and they showed a positive correlation with each other. High level of SNHG17 or LRPPRC was associated with worse survival of HCC patients. These data suggest that SNHG17 may inhibit c-Myc ubiquitination and thus enhance c-Myc level and facilitate proliferation by interacting with LRPPRC. Our findings identify a novel SNHG17-LRPPRC-c-Myc regulatory axis and elucidate its roles in G1/S transition and tumor growth, which may provide potential targets for cancer therapy.
致癌基因 c-Myc 是 G1/S 期转换的主要调节因子。长链非编码 RNA（lncRNA）作为各种细胞活动的新调节因子出现。在这里，我们发现 lncRNA snoRNA 宿主基因 17（SNHG17）在细胞周期的早期 G1 期升高。功能获得和缺失研究表明，SNHG17 增加了 c-Myc 蛋白水平，加速了 G1/S 期转换和细胞增殖，从而促进了体外和体内肿瘤细胞的生长。在机制上，SNHG17 的 1-150-nt 与富含亮氨酸的五肽重复蛋白（LRPPRC）蛋白的 1035-1369-aa 相互作用，破坏这种相互作用会削弱 SNHG17 对 c-Myc 表达、G1/S 期转换和细胞增殖的促进作用。沉默 c-Myc 或 LRPPRC 可减弱 SNHG17 刺激细胞增殖的作用。此外，沉默 SNHG17 或 LRPPRC 会增加泛素化 c-Myc 的水平并降低 c-Myc 蛋白的稳定性。对人肝细胞癌（HCC）组织的分析表明，SNHG17、LRPPRC 和 c-Myc 在 HCC 中均显著上调，并且它们彼此呈正相关。SNHG17 或 LRPPRC 水平高与 HCC 患者的生存预后较差相关。这些数据表明，SNHG17 可能通过与 LRPPRC 相互作用抑制 c-Myc 泛素化，从而提高 c-Myc 水平并促进增殖。我们的研究结果确定了一个新的 SNHG17-LRPPRC-c-Myc 调节轴，并阐明了其在 G1/S 期转换和肿瘤生长中的作用，这可能为癌症治疗提供潜在靶点。
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