TY - JOUR
T1 - BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo
AU - Kumar, Krishan
AU - DeCant, Brian T.
AU - Grippo, Paul J.
AU - Hwang, Rosa F.
AU - Bentrem, David J.
AU - Ebine, Kazumi
AU - Munshi, Hidayatullah G.
N1 - Funding Information:
This work was supported by grants (R01CA186885 and R01CA186885-S1 to HGM) from the National Cancer Institute, a Merit award (I01BX001363 to HGM) from the Department of Veterans Affairs, and an Acceleration Award from the Lurie Cancer Center.
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/2/9
Y1 - 2017/2/9
N2 - The fibrotic reaction, which can account for over 70%–80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs. We show that the inhibitory effect of pan-BET inhibitors on collagen I expression in primary cancer-associated PSCs is through blocking of BRD4 function. Importantly, we show that FOSL1 is repressed by BRD4 in primary cancer-associated PSCs and negatively regulates collagen I expression. While BET inhibitors do not affect viability or induce PSC apoptosis or senescence, BET inhibitors induce primary cancer-associated PSCs to become quiescent. Finally, we show that BET inhibitors attenuate stellate cell activation, fibrosis, and collagen I production in the EL-KrasG12D transgenic mouse model of pancreatic tumorigenesis. Our results demonstrate that BET inhibitors regulate fibrosis by modulating the activation and function of cancer-associated PSCs.
AB - The fibrotic reaction, which can account for over 70%–80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs. We show that the inhibitory effect of pan-BET inhibitors on collagen I expression in primary cancer-associated PSCs is through blocking of BRD4 function. Importantly, we show that FOSL1 is repressed by BRD4 in primary cancer-associated PSCs and negatively regulates collagen I expression. While BET inhibitors do not affect viability or induce PSC apoptosis or senescence, BET inhibitors induce primary cancer-associated PSCs to become quiescent. Finally, we show that BET inhibitors attenuate stellate cell activation, fibrosis, and collagen I production in the EL-KrasG12D transgenic mouse model of pancreatic tumorigenesis. Our results demonstrate that BET inhibitors regulate fibrosis by modulating the activation and function of cancer-associated PSCs.
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U2 - 10.1172/jci.insight.88032
DO - 10.1172/jci.insight.88032
M3 - Article
C2 - 28194432
AN - SCOPUS:85024474582
SN - 2379-3708
VL - 2
JO - JCI Insight
JF - JCI Insight
IS - 3
M1 - e88032
ER -