Li Zhe, Lu Xinyuan, Liu Yanfang, Zhao Jingjing, Ma Shengzhe, Yin Haoxiang, Huang Shenglin, Zhao Yingjun, He Xianghuo
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Hepatology. 2021 May;73(5):1764-1782. doi: 10.1002/hep.31530. Epub 2021 Mar 16.
Long noncoding RNAs (lncRNAs) are involved in almost every stage of tumor initiation and progression. Here, we have identified an antisense lncRNA, LINC00624, that arises from the antisense strand of chromo-domain-helicase-DNA-binding protein 1-like (CHD1L), located on chr1q21.1, with significant copy number gain and transcriptional activation of CHD1L and B-cell CLL/lymphoma 9 protein (BCL9), in hepatocellular carcinoma (HCC).
Overexpression of LINC00624 enhances tumor growth and metastasis in vitro and in vivo. Mechanistically, higher levels of LINC00624 strengthen the interaction between histone deacetylase 6 (HDAC6) and tripartite motif containing 28 (TRIM28), which accelerates HDAC6 ubiquitination and degradation. Moreover, LINC00624 binds to the RBCC domain of TRIM28, inhibits trimer formation, and weakens the interaction between TRIM28 and zinc finger protein 354C (ZNF354C). Thus, LINC00624 overexpression disrupts the formation of the HDAC6-TRIM28-ZNF354C transcriptional corepressor complex, resulting in the dissociation of the complex from the promoter of CHD1L and BCL9, thereby removing transcription inhibition.
Our findings suggest that LINC00624 acts as a molecular decoy that sequesters the HDAC6-TRIM28-ZNF354C transcriptional corepressor complex away from the specific genomic loci, and that it can potentially be a therapeutic target in HCC.
长链非编码RNA（lncRNA）几乎参与肿瘤起始和进展的每个阶段。在此，我们鉴定出一种反义lncRNA，即LINC00624，它由位于1号染色体q21.1区域的类染色质结构域解旋酶DNA结合蛋白1（CHD1L）的反义链产生，在肝细胞癌（HCC）中，CHD1L和B细胞淋巴瘤9蛋白（BCL9）存在显著的拷贝数增加和转录激活。
LINC00624的过表达在体外和体内均增强肿瘤生长和转移。机制上，较高水平的LINC00624增强组蛋白去乙酰化酶6（HDAC6）与含三联基序蛋白28（TRIM28）之间的相互作用，加速HDAC6的泛素化和降解。此外，LINC00624与TRIM28的RBCC结构域结合，抑制三聚体形成，并削弱TRIM28与锌指蛋白354C（ZNF354C）之间的相互作用。因此，LINC00624的过表达破坏了HDAC6-TRIM28-ZNF354C转录共抑制复合物的形成，导致该复合物从CHD1L和BCL9的启动子上解离，从而消除转录抑制。
我们的研究结果表明，LINC00624作为一种分子诱饵，将HDAC6-TRIM28-ZNF354C转录共抑制复合物从特定基因组位点上隔离，并且它可能是HCC的一个治疗靶点。
