State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China.
Nat Commun. 2024 Sep 27;15(1):8385. doi: 10.1038/s41467-024-52425-z.
The spatial co-presence of aberrant long non-coding RNAs (lncRNAs) and abnormal coding genes contributes to malignancy development in various tumors. However, precise coordinated mechanisms underlying this phenomenon in tumorigenesis remains incompletely understood. Here, we show that Prohibitin 2 (PHB2) orchestrates the transcription of an oncogenic CASC15-New-Isoform 2 (CANT2) lncRNA and the coding tumor-suppressor gene CCBE1, thereby accelerating melanoma tumorigenesis. In melanoma cells, PHB2 initially accesses the open chromatin sites at the CANT2 promoter, recruiting MLL2 to augment H3K4 trimethylation and activate CANT2 transcription. Intriguingly, PHB2 further binds the activated CANT2 transcript, targeting the promoter of the tumor-suppressor gene CCBE1. This interaction recruits histone deacetylase HDAC1 to decrease H3K27 acetylation at the CCBE1 promoter and inhibit its transcription, significantly promoting tumor cell growth and metastasis both in vitro and in vivo. Our study elucidates a PHB2-mediated mechanism that orchestrates the aberrant transcription of lncRNAs and coding genes, providing an intriguing epigenetic regulatory model in tumorigenesis.
异常长非编码 RNA（lncRNA）和异常编码基因的空间共存有助于各种肿瘤的恶性发展。然而，肿瘤发生中这种现象背后的确切协调机制仍不完全清楚。在这里，我们表明 Prohibitin 2（PHB2）协调致癌 CASC15-New-Isoform 2（CANT2）lncRNA 和编码肿瘤抑制基因 CCBE1 的转录，从而加速黑色素瘤肿瘤发生。在黑色素瘤细胞中，PHB2 最初访问 CANT2 启动子的开放染色质位点，招募 MLL2 以增加 H3K4 三甲基化并激活 CANT2 转录。有趣的是，PHB2 进一步结合激活的 CANT2 转录本，靶向肿瘤抑制基因 CCBE1 的启动子。这种相互作用招募组蛋白去乙酰化酶 HDAC1 以减少 CCBE1 启动子处的 H3K27 乙酰化并抑制其转录，显著促进体外和体内肿瘤细胞的生长和转移。我们的研究阐明了 PHB2 介导的协调 lncRNA 和编码基因异常转录的机制，为肿瘤发生提供了一个有趣的表观遗传调控模型。
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