Format

Send to

Choose Destination
See comment in PubMed Commons below
Mol Cell. 2016 Apr 7;62(1):34-46. doi: 10.1016/j.molcel.2016.03.013.

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

Author information

1
Howard Hughes Medical Institute, Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
2
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
4
Department of Pathology, Brigham & Women's Hospital, Boston, MA 02215, USA.
5
Departments of Medicine, Microbiology, and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Department of Pharmacology, School of Medicine, Yale University, New Haven, CT 06520, USA.
7
Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
8
Cancer Research Institute, Beth Israel Deaconess Cancer Center, and Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
9
Cancer Research Institute, Beth Israel Deaconess Cancer Center, and Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
10
Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
11
Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
12
Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
13
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA.
14
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
15
Howard Hughes Medical Institute, Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: zon@enders.tch.harvard.edu.

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.

PMID:
27058786
PMCID:
PMC4836061
[Available on 2017-04-07]
DOI:
10.1016/j.molcel.2016.03.013
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center