PMID- 35504112
OWN - NLM
STAT- MEDLINE
DCOM- 20220510
LR  - 20240214
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 29
DP  - 2022 Jul
TI  - Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes 
      oncogenic functions in HPV16 positive head and neck cancer.
PG  - 100799
LID - S1476-5586(22)00026-4 [pii]
LID - 10.1016/j.neo.2022.100799 [doi]
LID - 100799
AB  - Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer 
      worldwide and incidence rates are continuing to rise globally. Patients often 
      present with locally advanced disease and a staggering 50% chance of relapse 
      following treatment. Aberrant activation of adaptive response signaling pathways, 
      such as the cAMP/PKA pathway, induce an array of genes associated with known 
      cancer pathways that promote tumorigenesis and drug resistance. We identified the 
      cAMP Regulated Transcription Coactivator 2 (CRTC2) to be overexpressed and 
      constitutively activated in HNSCCs and this confers poor prognosis. CRTCs are 
      regulated through their subcellular localization and we show that CRTC2 is 
      exclusively nuclear in HPV(+) HNSCC, thus constitutively active, due to 
      non-canonical Mitogen-Activated Kinase Kinase 1 (MEKK1)-mediated activation via a 
      MEKK1-p38 signaling axis. Loss-of-function and pharmacologic inhibition 
      experiments decreased CRTC2/CREB transcriptional activity by reducing nuclear 
      CRTC2 via nuclear import inhibition and/or by eviction of CRTC2 from the nucleus. 
      This shift in localization was associated with decreased proliferation, 
      migration, and invasion. Our results suggest that small molecules that inhibit 
      nuclear CRTC2 and p38 activity may provide therapeutic benefit to patients with 
      HPV(+) HNSCC.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Carper, Miranda B
AU  - Carper MB
AD  - Lineberger Comprehensive Cancer Center, UNC School of Medicine, The University of 
      North Carolina at Chapel Hill, NC, USA.
FAU - Goel, Saumya
AU  - Goel S
AD  - Oral and Craniofacial Health Sciences, Adams School of Dentistry, The University 
      of North Carolina at Chapel Hill, NC, USA; Carolina Research Scholar, 
      Undergraduate Curriculum in Biochemistry, The University of North Carolina at 
      Chapel Hill, NC, USA.
FAU - Zhang, Anna M
AU  - Zhang AM
AD  - Oral and Craniofacial Health Sciences, Adams School of Dentistry, The University 
      of North Carolina at Chapel Hill, NC, USA.
FAU - Damrauer, Jeffrey S
AU  - Damrauer JS
AD  - Lineberger Comprehensive Cancer Center, UNC School of Medicine, The University of 
      North Carolina at Chapel Hill, NC, USA.
FAU - Cohen, Stephanie
AU  - Cohen S
AD  - Pathology Services Core, Lineberger Comprehensive Cancer Center, UNC School of 
      Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, Chapel 
      Hill, NC, USA.
FAU - Zimmerman, Matthew P
AU  - Zimmerman MP
AD  - Graduate Curriculum in Genetics & Molecular Biology, Biological & Biomedical 
      Sciences Program, UNC School of Medicine, The University of North Carolina at 
      Chapel Hill, NC, USA.
FAU - Gentile, Gabrielle M
AU  - Gentile GM
AD  - Graduate Curriculum in Genetics & Molecular Biology, Biological & Biomedical 
      Sciences Program, UNC School of Medicine, The University of North Carolina at 
      Chapel Hill, NC, USA.
FAU - Parag-Sharma, Kshitij
AU  - Parag-Sharma K
AD  - Graduate Curriculum in Cell Biology & Physiology, Biological & Biomedical 
      Sciences Program, UNC School of Medicine, The University of North Carolina at 
      Chapel Hill, NC, USA.
FAU - Murphy, Ryan M
AU  - Murphy RM
AD  - Graduate Curriculum in Pharmacology, Biological & Biomedical Sciences Program, 
      UNC School of Medicine, The University of North Carolina at Chapel Hill, NC, USA.
FAU - Sato, Kotaro
AU  - Sato K
AD  - Lineberger Comprehensive Cancer Center, UNC School of Medicine, The University of 
      North Carolina at Chapel Hill, NC, USA; Department of Oral and Maxillofacial 
      Surgery, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
FAU - Nickel, Kwangok P
AU  - Nickel KP
AD  - Department of Human Oncology and UW Carbone Cancer Center, School of Medicine and 
      Public Health, University of Wisconsin, Madison, WI, USA.
FAU - Kimple, Randall J
AU  - Kimple RJ
AD  - Department of Human Oncology and UW Carbone Cancer Center, School of Medicine and 
      Public Health, University of Wisconsin, Madison, WI, USA.
FAU - Yarbrough, Wendell G
AU  - Yarbrough WG
AD  - Lineberger Comprehensive Cancer Center, UNC School of Medicine, The University of 
      North Carolina at Chapel Hill, NC, USA; Department of Otolaryngology/Head and 
      Neck Surgery, University of North Carolina School of Medicine, Chapel Hill, North 
      Carolina, Chapel Hill, NC, USA; Department of Pathology, University of North 
      Carolina School of Medicine, Chapel Hill, North Carolina, Chapel Hill, NC, USA.
FAU - Amelio, Antonio L
AU  - Amelio AL
AD  - Department of Cell Biology and Physiology, UNC School of Medicine, University of 
      North Carolina at Chapel Hill, Chapel Hill, NC, USA; Biomedical Research Imaging 
      Center, UNC School of Medicine, The University of North Carolina at Chapel Hill, 
      NC, USA; Lineberger Comprehensive Cancer Center, Cancer Cell Biology Program, UNC 
      School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 
      USA. Electronic address: antonio_amelio@unc.edu.
LA  - eng
GR  - P50 DE026787/DE/NIDCR NIH HHS/United States
GR  - F31 DE028749/DE/NIDCR NIH HHS/United States
GR  - P30 CA014520/CA/NCI NIH HHS/United States
GR  - R01 DE030123/DE/NIDCR NIH HHS/United States
GR  - T90 DE021986/DE/NIDCR NIH HHS/United States
GR  - P50 DE030707/DE/NIDCR NIH HHS/United States
GR  - T32 CA211056/CA/NCI NIH HHS/United States
GR  - T32 GM119999/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220430
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (CRTC2 protein, human)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Mitogens)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Carcinogenesis
MH  - Cyclic AMP Response Element-Binding Protein/genetics/metabolism
MH  - *Head and Neck Neoplasms/genetics
MH  - Humans
MH  - Mitogens
MH  - Neoplasm Recurrence, Local
MH  - *Papillomavirus Infections/complications/genetics
MH  - Squamous Cell Carcinoma of Head and Neck/genetics
MH  - Transcription Factors/genetics
PMC - PMC9065880
OTO - NOTNLM
OT  - CREB
OT  - HPV(+) oropharyngeal cancer
OT  - Head and neck cancer
OT  - cAMP Regulated transcription coactivators
COIS- Declaration of Competing Interest A.L.A. is a Global Advisory Board member and 
      paid consultant for LG Chem Life Sciences Innovation Center. All other authors 
      declare no potential conflicts of interest.
EDAT- 2022/05/04 06:00
MHDA- 2022/05/11 06:00
PMCR- 2022/04/30
CRDT- 2022/05/03 18:16
PHST- 2021/12/31 00:00 [received]
PHST- 2022/04/14 00:00 [revised]
PHST- 2022/04/14 00:00 [accepted]
PHST- 2022/05/04 06:00 [pubmed]
PHST- 2022/05/11 06:00 [medline]
PHST- 2022/05/03 18:16 [entrez]
PHST- 2022/04/30 00:00 [pmc-release]
AID - S1476-5586(22)00026-4 [pii]
AID - 100799 [pii]
AID - 10.1016/j.neo.2022.100799 [doi]
PST - ppublish
SO  - Neoplasia. 2022 Jul;29:100799. doi: 10.1016/j.neo.2022.100799. Epub 2022 Apr 30.