Wang Yingchao, Zhong Yue, Zheng Xiaoyuan, Cheng Niangmei, Yang Yong, Yang Ye, Wang Fei, Zhuang Qiuyu, Huang Yao, Guo Wuhua, Liao Naishun, Yang Xiaoyu, Zhao Bixing, Liu Xiaolong
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China.
Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou, 350025, P. R. China.
Cell Death Discov. 2023 Aug 26;9(1):316. doi: 10.1038/s41420-023-01620-w.
The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA's specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which might provide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.
N6-甲基腺苷（m6A）RNA甲基转移酶METTL16是RNA修饰领域中一个新出现的作用因子，负责在少数转录本中沉积m6A。极光激酶A（AURKA）已被确认为包括肝细胞癌（HCC）在内的癌症发展中的一种癌基因。然而，尚不清楚METTL16介导的长链非编码RNA（lncRNA）的m6A修饰是否能在癌症进展中调节AURKA的激活。在这里，我们旨在研究lncRNA与AURKA信号传导和HCC进展中的m6A修饰之间的功能联系。在这里，我们发现长链非编码RNA TIALD（诱导AURKA溶酶体降解的转录本）在HCC组织中因METTL16介导的m6A甲基化而下调，以促进其RNA降解，并且与不良预后相关。功能分析表明，TIALD在体外和体内均抑制HCC转移。机制上，TIALD直接与AURKA相互作用，并通过溶酶体途径促进其降解，从而抑制HCC的上皮-间质转化和转移。AURKA的特异性抑制剂alisertib对低TIALD表达的肝癌具有有效的治疗作用，这可能为HCC治疗提供新的见解。我们的研究揭示了METTL16-TIALD-AURKA轴的负性功能环，并确定了METTL16介导的m6A诱导的TIALD降解对HCC进展中AURKA信号传导的新机制，这可能为HCC提供潜在的预后和治疗靶点。
