Nucleotide stress induction of HEXIM1 suppresses melanoma by modulating cancer cell-specific gene transcription [RNA-Seq2]

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 Tet-On HEXIM1-inducible A375 melanoma cells treated with either DMSO or 1 µg/mL doxycycline in triplicate for 48 hrs.

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Tan JL, Fogley RD, Flynn RA, Ablain J, Yang S, Saint-André V, Fan ZP, Do BT, Laga AC, Fujinaga K, Santoriello C, Greer CB, Kim YJ, Clohessy JG, Bothmer A, Pandell N, Avagyan S, Brogie JE, van Rooijen E, Hagedorn EJ, Shyh-Chang N, White RM, Price DH, Pandolfi PP, Peterlin BM, Zhou Y, Kim TH, Asara JM, Chang HY, Young RA, Zon LI