title: Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma.
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.
authors.affiliation: 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.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Fogley
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Flynn
authors.affiliation: 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.
authors.forename: Julien
authors.initials: J
authors.lastname: Ablain
authors.affiliation: 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.
authors.forename: Song
authors.initials: S
authors.lastname: Yang
authors.affiliation: Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Violaine
authors.initials: V
authors.lastname: Saint-André
authors.affiliation: Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Zi Peng
authors.initials: ZP
authors.lastname: Fan
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Do
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, MA 02215, USA.
authors.forename: Alvaro C
authors.initials: AC
authors.lastname: Laga
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Koh
authors.initials: K
authors.lastname: Fujinaga
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Santoriello
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Celeste B
authors.initials: CB
authors.lastname: Greer
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: John G
authors.initials: JG
authors.lastname: Clohessy
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Bothmer
authors.affiliation: Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pandell
authors.affiliation: 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.
authors.forename: Serine
authors.initials: S
authors.lastname: Avagyan
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Brogie
authors.affiliation: 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.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Rooijen
authors.affiliation: 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.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Hagedorn
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.affiliation: Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: White
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Price
authors.affiliation: 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.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: B Matija
authors.initials: BM
authors.lastname: Peterlin
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: 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.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental; D015513:Oncogene Proteins / Q000235:genetics; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics*; D011743:Pyrimidines / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C476123:HEXIM1 protein, human; D015513:Oncogene Proteins; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; D042925:Positive Transcriptional Elongation Factor B