Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment

Yinshi Huang, Sabikun Nahar, Akifumi Nakagawa, Maite G. Fernandez-Barrena, Jennifer A. Mertz, Barbara M. Bryant, Curtis E. Adams, Mari Mino-Kenudson, Kate N. Von Alt, Kevin Chang, Andrew R. Conery, Charlie Hatton, Robert J. Sims, Martin E. Fernandez-Zapico, Xingpeng Wang, Keith D. Lillemoe, Carlos Fernáandez Del Castillo, Andrew L. Warshaw, Sarah P Thayer, Andrew S. Liss

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors.BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC.

Original languageEnglish (US)
Pages (from-to)4259-4270
Number of pages12
JournalClinical Cancer Research
Volume22
Issue number16
DOIs
StatePublished - Aug 15 2016

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Tumor Microenvironment
Pancreatic Neoplasms
Adenocarcinoma
Growth
Heterografts
Epigenomics
Neoplasms
Small Interfering RNA
Proteins
Immunoprecipitation
Genes
Chromatin
Research Design
Transcription Factors
Down-Regulation
Maintenance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Huang, Y., Nahar, S., Nakagawa, A., Fernandez-Barrena, M. G., Mertz, J. A., Bryant, B. M., ... Liss, A. S. (2016). Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment. Clinical Cancer Research, 22(16), 4259-4270. https://doi.org/10.1158/1078-0432.CCR-15-2068

Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment. / Huang, Yinshi; Nahar, Sabikun; Nakagawa, Akifumi; Fernandez-Barrena, Maite G.; Mertz, Jennifer A.; Bryant, Barbara M.; Adams, Curtis E.; Mino-Kenudson, Mari; Von Alt, Kate N.; Chang, Kevin; Conery, Andrew R.; Hatton, Charlie; Sims, Robert J.; Fernandez-Zapico, Martin E.; Wang, Xingpeng; Lillemoe, Keith D.; Castillo, Carlos Fernáandez Del; Warshaw, Andrew L.; Thayer, Sarah P; Liss, Andrew S.

In: Clinical Cancer Research, Vol. 22, No. 16, 15.08.2016, p. 4259-4270.

Research output: Contribution to journalArticle

Huang, Y, Nahar, S, Nakagawa, A, Fernandez-Barrena, MG, Mertz, JA, Bryant, BM, Adams, CE, Mino-Kenudson, M, Von Alt, KN, Chang, K, Conery, AR, Hatton, C, Sims, RJ, Fernandez-Zapico, ME, Wang, X, Lillemoe, KD, Castillo, CFD, Warshaw, AL, Thayer, SP & Liss, AS 2016, 'Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment', Clinical Cancer Research, vol. 22, no. 16, pp. 4259-4270. https://doi.org/10.1158/1078-0432.CCR-15-2068
Huang, Yinshi ; Nahar, Sabikun ; Nakagawa, Akifumi ; Fernandez-Barrena, Maite G. ; Mertz, Jennifer A. ; Bryant, Barbara M. ; Adams, Curtis E. ; Mino-Kenudson, Mari ; Von Alt, Kate N. ; Chang, Kevin ; Conery, Andrew R. ; Hatton, Charlie ; Sims, Robert J. ; Fernandez-Zapico, Martin E. ; Wang, Xingpeng ; Lillemoe, Keith D. ; Castillo, Carlos Fernáandez Del ; Warshaw, Andrew L. ; Thayer, Sarah P ; Liss, Andrew S. / Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 16. pp. 4259-4270.
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abstract = "Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors.BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC.",
author = "Yinshi Huang and Sabikun Nahar and Akifumi Nakagawa and Fernandez-Barrena, {Maite G.} and Mertz, {Jennifer A.} and Bryant, {Barbara M.} and Adams, {Curtis E.} and Mari Mino-Kenudson and {Von Alt}, {Kate N.} and Kevin Chang and Conery, {Andrew R.} and Charlie Hatton and Sims, {Robert J.} and Fernandez-Zapico, {Martin E.} and Xingpeng Wang and Lillemoe, {Keith D.} and Castillo, {Carlos Fern{\'a}andez Del} and Warshaw, {Andrew L.} and Thayer, {Sarah P} and Liss, {Andrew S.}",
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T1 - Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment

AU - Huang, Yinshi

AU - Nahar, Sabikun

AU - Nakagawa, Akifumi

AU - Fernandez-Barrena, Maite G.

AU - Mertz, Jennifer A.

AU - Bryant, Barbara M.

AU - Adams, Curtis E.

AU - Mino-Kenudson, Mari

AU - Von Alt, Kate N.

AU - Chang, Kevin

AU - Conery, Andrew R.

AU - Hatton, Charlie

AU - Sims, Robert J.

AU - Fernandez-Zapico, Martin E.

AU - Wang, Xingpeng

AU - Lillemoe, Keith D.

AU - Castillo, Carlos Fernáandez Del

AU - Warshaw, Andrew L.

AU - Thayer, Sarah P

AU - Liss, Andrew S.

PY - 2016/8/15

Y1 - 2016/8/15

N2 - Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors.BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC.

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