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Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

Justin l. Tan 1, 2, 3, 4, 5 Rachel d. Fogley 1, 2, 3, 4, 5 Ryan a. Flynn 6 Julien Ablain 1, 2, 3, 4, 5 Song Yang 1, 2, 3, 4, 5 Violaine Saint-André 7, 8 Zi peng Fan 7, 8 Brian t. Do 6 Alvaro c. Laga 9 Koh Fujinaga 10 Cristina Santoriello 1, 2, 3, 4, 5 Celeste b. Greer 11 Yoon jung Kim 12 John g. Clohessy 13, 14 Anne Bothmer 14, 13 Nicole Pandell 13 Serine Avagyan 1, 2, 3, 4, 5 John e. Brogie 15 Ellen Van rooijen 1, 2, 3, 4, 5 Elliott j. Hagedorn 1, 2, 3, 4, 5 Ng Shyh-Chang 16 Richard m. White 17, 18 David h. Price 15 Pier paolo Pandolfi 13, 14 B. matija Peterlin 10 Yi Zhou 1, 2, 3, 4, 5 Tae hoon Kim 12 John m. Asara 13 Howard y. Chang 6 Richard a. Young 7, 8 Leonard i. Zon 1, 2, 3, 4, 5, *
Abstract : Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02871949
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Submitted on : Wednesday, June 17, 2020 - 1:41:08 PM
Last modification on : Friday, July 17, 2020 - 11:03:45 AM

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Justin l. Tan, Rachel d. Fogley, Ryan a. Flynn, Julien Ablain, Song Yang, et al.. Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma. Molecular Cell, Elsevier, 2016, 62 (1), pp.34-46. ⟨10.1016/j.molcel.2016.03.013⟩. ⟨pasteur-02871949⟩

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