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Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer
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 signali...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065880/ https://www.ncbi.nlm.nih.gov/pubmed/35504112 http://dx.doi.org/10.1016/j.neo.2022.100799 |
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author | Carper, Miranda B. Goel, Saumya Zhang, Anna M. Damrauer, Jeffrey S. Cohen, Stephanie Zimmerman, Matthew P. Gentile, Gabrielle M. Parag-Sharma, Kshitij Murphy, Ryan M. Sato, Kotaro Nickel, Kwangok P. Kimple, Randall J. Yarbrough, Wendell G. Amelio, Antonio L. |
author_facet | Carper, Miranda B. Goel, Saumya Zhang, Anna M. Damrauer, Jeffrey S. Cohen, Stephanie Zimmerman, Matthew P. Gentile, Gabrielle M. Parag-Sharma, Kshitij Murphy, Ryan M. Sato, Kotaro Nickel, Kwangok P. Kimple, Randall J. Yarbrough, Wendell G. Amelio, Antonio L. |
author_sort | Carper, Miranda B. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9065880 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-90658802022-05-16 Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer Carper, Miranda B. Goel, Saumya Zhang, Anna M. Damrauer, Jeffrey S. Cohen, Stephanie Zimmerman, Matthew P. Gentile, Gabrielle M. Parag-Sharma, Kshitij Murphy, Ryan M. Sato, Kotaro Nickel, Kwangok P. Kimple, Randall J. Yarbrough, Wendell G. Amelio, Antonio L. Neoplasia Original article 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. Neoplasia Press 2022-04-30 /pmc/articles/PMC9065880/ /pubmed/35504112 http://dx.doi.org/10.1016/j.neo.2022.100799 Text en © 2022 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Carper, Miranda B. Goel, Saumya Zhang, Anna M. Damrauer, Jeffrey S. Cohen, Stephanie Zimmerman, Matthew P. Gentile, Gabrielle M. Parag-Sharma, Kshitij Murphy, Ryan M. Sato, Kotaro Nickel, Kwangok P. Kimple, Randall J. Yarbrough, Wendell G. Amelio, Antonio L. Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer |
title | Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer |
title_full | Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer |
title_fullStr | Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer |
title_full_unstemmed | Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer |
title_short | Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer |
title_sort | activation of the creb coactivator crtc2 by aberrant mitogen signaling promotes oncogenic functions in hpv16 positive head and neck cancer |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065880/ https://www.ncbi.nlm.nih.gov/pubmed/35504112 http://dx.doi.org/10.1016/j.neo.2022.100799 |
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