Nucleotide stress induction of HEXIM1 suppresses melanoma by modulating cancer cell-specific gene transcription [RNA-Seq1]

Cancer metabolism has been actively studied to gain insights into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a novel melanoma suppressor that participates in nucleotide stress regulation. HEXIM1 expression is low in melanoma. Its overexpression suppresses melanoma while its inactivation accelerates tumor onset in vivo. HEXIM1 responds to nucleotide stress. Knockdown of HEXIM1 rescues neural crest and melanoma nucleotide stress phenotypes in vivo. Mechanistically, under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to pause transcription at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic transcripts to bind to and be stabilized by HEXIM1. HEXIM1 therefore plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals a novel role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma. Overall design: RNA-seq analysis of human A375 melanoma cells treated with either DMSO or 25 µM A771726 for 0-72 hrs.

癌症代谢领域的研究长期受到广泛关注，旨在深入解析肿瘤发生相关的存活机制与易感特性。在黑色素瘤中，本研究鉴定出转录延伸调控因子HEXIM1（HEXIM1）作为一种新型黑色素瘤抑制因子，其参与核苷酸应激的调控过程。黑色素瘤组织中HEXIM1的表达水平较低。过表达HEXIM1可抑制黑色素瘤进展，而其功能失活则会在体内加速肿瘤发生。HEXIM1可响应核苷酸应激，体内实验表明，敲低HEXIM1能够挽救神经嵴与黑色素瘤的核苷酸应激表型。从机制层面来看，在核苷酸应激条件下，HEXIM1会被诱导与启动转录延伸的激酶P-TEFb形成抑制性复合物，从而使肿瘤发生相关基因的转录过程停滞。由此引发的基因表达改变，还会使抗肿瘤发生的转录本结合HEXIM1并被其稳定。因此，HEXIM1在抑制癌细胞特异性基因转录的同时，还能促进抗癌相关基因的表达，发挥关键调控作用。本研究揭示了HEXIM1在黑色素瘤中连接核苷酸代谢与转录调控的全新功能。实验整体设计：对分别经二甲基亚砜（DMSO）或25 μM A771726处理0至72小时的人A375黑色素瘤细胞进行RNA测序（RNA-seq）分析。