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BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo
Krishan Kumar, … , Kazumi Ebine, Hidayatullah G. Munshi
Krishan Kumar, … , Kazumi Ebine, Hidayatullah G. Munshi
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e88032. https://doi.org/10.1172/jci.insight.88032.
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Research Article Gastroenterology Oncology

BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo

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Abstract

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.

Authors

Krishan Kumar, Brian T. DeCant, Paul J. Grippo, Rosa F. Hwang, David J. Bentrem, Kazumi Ebine, Hidayatullah G. Munshi

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Figure 1

BET inhibitors decrease collagen I production by primary PSCs isolated from human PDAC tumors.

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BET inhibitors decrease collagen I production by primary PSCs isolated f...
(A) Human PDAC tumor sections were stained for α-SMA and BRD4 by immunofluorescence, and nuclei were counterstained using DAPI. Original magnification, ×40 (left); ×100 (right). (B) An immortalized human pancreatic stellate cell line was treated with the BET inhibitors JQ1 (1 μM) and I-BET151 (1 μM), and the effect on COL1A1 and COL1A2 mRNA expression was determined by qRT-PCR (n = 4). ***P < 0.001. Data were analyzed by 2-tailed unpaired Student’s t test. The effect on collagen I protein expression was determined by Western blotting. These results are representative of 4 (n = 4) independent experiments. (C and D) Early-passage cancer-associated primary PSCs, which were isolated from deidentified human PDAC specimens using the outgrowth assay, were treated with the BET inhibitors JQ1 (1 μM) and I-BET151 (1 μM). The effect on COL1A1 and COL1A2 mRNA expression was determined by qRT-PCR (n = 4). ***P < 0.001. Data were analyzed by 2-tailed unpaired Student’s t test. The effect on collagen I protein expression was determined by Western blotting. These results are representative of 4 (n = 4) independent experiments. BET, bromodomain and extraterminal; COL, collagen; PDAC, pancreatic ductal adenocarcinoma; PSCs, pancreatic stellate cells; α-SMA, α–smooth muscle actin.

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