Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Clin Transl Med. 2022 Nov;12(11):e1107. doi: 10.1002/ctm2.1107.
Hepatocellular carcinoma (HCC) ranks fourth among the malignancies leading to cancer-related deaths all around the world. It is increasingly evident that long non-coding RNAs (lncRNAs) are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N -methyladenosine (m A) regulates gene expression by impacting multiple aspects of mRNA metabolism. However, there are still no reports on genome-wide screening and functional annotation of m A-methylated lncRNAs in HCC.
The m A modification and biologic functions of ARHGAP5-AS1 in HCC were investigated through a series of biochemical assays. Clinical implications of ARHGAP5-AS1 were examined in tissues from HCC patients.
After systematically analysing the m A-seq data of HCC cells, we identified 22 candidate lncRNAs with evidently dysregulated m A levels. Among these lncRNAs, we found that ARHGAP5-AS1 is the lncRNA with the highest levels of m A modification and significantly increased expression in HCC specimens. METTL14 acts as the m A writer of ARHGAP5-AS1 and IGF2BP2 stabilises the lncRNA as its m A reader. ARHGAP5-AS1 remarkably promotes malignant behaviours of HCC cells ex vivo and in vivo. We identified oncoprotein CSDE1 working as the interacting protein of the lncRNA and TRIM28 as the E3 ligase of CSDE1 in HCC. Interestingly, ARHGAP5-AS1 could attenuate interactions between CSDE1 and TRIM28, which prevents the degradation of CSDE1 via the ubiquitin-proteasome pathway. Elevated levels of CSDE1 coordinate oncogenic RNA regulons, promote translation of VIM and RAC1 and activate the ERK pathway, which contributes to HCC prognosis.
Our study reveals a new paradigm in m A-modified lncRNAs controlling CSDE1-mediated oncogenic RNA regulons and highlights lncRNAs as potential targets for future therapeutics against HCC.
肝细胞癌（HCC）在全球范围内导致癌症相关死亡的恶性肿瘤中排名第四。越来越多的证据表明，长链非编码 RNA（lncRNA）是肝癌发生的关键模式。作为最普遍的 mRNA 修饰形式，N6-甲基腺苷（m A）通过影响 mRNA 代谢的多个方面来调节基因表达。然而，目前尚无关于 HCC 中 m A 修饰的 lncRNA 的全基因组筛选和功能注释的报道。
通过一系列生化测定研究了 ARHGAP5-AS1 在 HCC 中的 m A 修饰和生物学功能。在 HCC 患者的组织中检测了 ARHGAP5-AS1 的临床意义。
在系统分析 HCC 细胞的 m A-seq 数据后，我们鉴定出 22 个候选 lncRNA，它们的 m A 水平明显失调。在这些 lncRNA 中，我们发现 ARHGAP5-AS1 是 m A 修饰水平最高且在 HCC 标本中表达显著增加的 lncRNA。METTL14 作为 ARHGAP5-AS1 的 m A 写入器，IGF2BP2 作为其 m A 读取器稳定该 lncRNA。ARHGAP5-AS1 显著促进 HCC 细胞的体外和体内恶性行为。我们确定癌蛋白 CSDE1 作为 lncRNA 的相互作用蛋白，TRIM28 作为 HCC 中 CSDE1 的 E3 连接酶。有趣的是，ARHGAP5-AS1 可以减弱 CSDE1 和 TRIM28 之间的相互作用，从而阻止 CSDE1 通过泛素-蛋白酶体途径降解。CSDE1 的上调水平协调致癌 RNA 调控子，促进 VIM 和 RAC1 的翻译，并激活 ERK 途径，从而影响 HCC 的预后。
本研究揭示了 m A 修饰的 lncRNA 控制 CSDE1 介导的致癌 RNA 调控子的新范式，并强调了 lncRNA 作为未来 HCC 治疗的潜在靶点。
