Bidirectional transcription of Linc00441 and RB1 via H3K27 modification-dependent way promotes hepatocellular carcinoma.
Bidirectional transcription of Linc00441 and RB1 via H3K27 modification-dependent way promotes hepatocellular carcinoma.
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Linc00441和RB1通过H3K27修饰依赖方式双向转录促进肝细胞癌
DOI：
10.1038/cddis.2017.81
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发表时间：
2017-03-16
影响因子：
9
通讯作者：
Sun B
中科院分区：
文献类型：
--
作者：
Tang J;Xie Y;Xu X;Yin Y;Jiang R;Deng L;Tan Z;Gangarapu V;Tang J;Sun B
视网膜母细胞瘤基因 (RB1) 是一种已知的肿瘤抑制基因 (TSG)，在包括肝细胞癌 (HCC) 在内的多种癌症中含量降低。在这里，我们重点关注具有邻居基因 RB1 的双向转录长非编码 RNA (Linc00441)，以研究 Linc00441 是否参与 HCC 中 RB1 的抑制。我们发现异常上调的核内 Linc00441 与人类 HCC 样本中的 RB1 表达呈负相关。功能获得和丧失的研究表明，Linc00441 可以在体外和体内促进 HCC 细胞的增殖，并抑制细胞凋亡和细胞周期重排。此外，RNA Pull-down 测定表明 Linc00441 诱导的 RB1 水平降低与 Linc00441 招募的 DNMT3A 偶然甲基化有关。相反，转录因子（TCF-4）增强H3K27乙酰化，Linc00441的直接转录因子负责HCC中Linc00441的上调。总之，Linc00441和双向转录的邻居RB1之间的表观遗传相互作用可能是HCC中RB1失活的从头理论切点，并可能作为未来肿瘤治疗的靶向位点。
The retinoblastoma gene (RB1), a known tumor-suppressor gene (TSG), was decreased in multiple cancers including hepatocellular carcinoma (HCC). Here we focused on the bidirectional transcripted long noncoding RNA (Linc00441) with neighbor gene RB1 to investigate whether Linc00441 is involved in the suppression of RB1 in HCC. We found that aberrant upregulated intranuclear Linc00441 was reversely correlated with RB1 expression in human HCC samples. The gain-and loss-of-function investigation revealed that Linc00441 could promote the proliferation of HCC cells in vitro and in vivo with an apoptosis suppression and cell cycle rearrangement. Furthermore, RNA pull-down assay indicated the decreased level of RB1 induced by Linc00441 was associated with the incidental methylation by DNMT3A recruited by Linc00441. On the contrary, the transcription factor (TCF-4) enhanced H3K27 acetylation and direct transcription factor for Linc00441 was responsible for the upregulation of Linc00441 in HCC. In conclusion, the epigenetic interaction between Linc00441 and bidirectional transcripted neighbor RB1 may be a de novo theory cutting-point for the inactivation of RB1 in HCC and may serve as targeting site for tumor therapy in the future.