Journal article
Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma
Molecular cell, Vol.62(1), pp.34-46
04/2016
DOI: 10.1016/j.molcel.2016.03.013
PMCID: PMC4836061
PMID: 27058786
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.
Details
- Title: Subtitle
- Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma
- Creators
- Justin L Tan - Harvard Stem Cell Institute [Cambridge, USA]Rachel D Fogley - Harvard Stem Cell Institute [Cambridge, USA]Ryan A Flynn - Center for Personal Dynamic Regulomes [Stanford, USA]Julien Ablain - Harvard Stem Cell Institute [Cambridge, USA]Song Yang - Harvard Stem Cell Institute [Cambridge, USA]Violaine Saint-André - Whitehead InstituteZi Peng Fan - Whitehead InstituteBrian T Do - Center for Personal Dynamic Regulomes [Stanford, USA]Alvaro C Laga - Brigham & Women’s Hospital [Boston]Koh Fujinaga - University of California [San Francisco]Cristina Santoriello - Harvard Stem Cell Institute [Cambridge, USA]Celeste B Greer - Yale University School of MedicineYoon Jung Kim - University of Texas at Dallas [Richardson]John G Clohessy - Beth Israel Deaconess Medical Center [Boston]Anne Bothmer - Cancer Research Institute [Boston, USA]Nicole Pandell - Beth Israel Deaconess Medical Center [Boston]Serine Avagyan - Harvard Stem Cell Institute [Cambridge, USA]John E Brogie - University of Iowa [Iowa City]Ellen van Rooijen - Harvard Stem Cell Institute [Cambridge, USA]Elliott J Hagedorn - Harvard Stem Cell Institute [Cambridge, USA]Ng Shyh-Chang - Genome Institute of SingaporeRichard M White - Memorial Sloane Kettering Cancer Center [New York]David H Price - University of Iowa [Iowa City]Pier Paolo Pandolfi - Beth Israel Deaconess Medical Center [Boston]B. Matija Peterlin - University of California [San Francisco]Yi Zhou - Harvard Stem Cell Institute [Cambridge, USA]Tae Hoon Kim - University of Texas at Dallas [Richardson]John M Asara - Beth Israel Deaconess Medical Center [Boston]Howard Y Chang - Center for Personal Dynamic Regulomes [Stanford, USA]Richard A Young - Whitehead InstituteLeonard I Zon - Harvard Stem Cell Institute [Cambridge, USA]
- Resource Type
- Journal article
- Publication Details
- Molecular cell, Vol.62(1), pp.34-46
- Publisher
- Elsevier
- DOI
- 10.1016/j.molcel.2016.03.013
- PMID
- 27058786
- PMCID
- PMC4836061
- ISSN
- 1097-2765
- eISSN
- 1097-4164
- Language
- English
- Date published
- 04/2016
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984025280302771
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