Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. While the genetic alterations of PDAC have been well characterized, the epigenetic pathways regulating PDAC remain, for the most part, elusive. Employing an in vivo shRNA screen targeting epigenetic regulators, we identified members of the BET family of chromatin adaptors as key regulators of PDAC cell growth and maintenance of the tumor stroma. BET family members contribute to PDAC cell growth by modulating the activity of two key transcriptional programs, MYC and GLI. Within the cancer cells, BET inhibition also results in down-regulation of a key mediator of the tumor microenvironment, SHH, corresponding to a decrease in the stromal content of tumors. Taken together, these results suggest that therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Total RNA was isolated from 4 untreated PDAC cell lines or those exposedto the BET bromodomain inhibibitor CPI203 (1.6 uM) or control DMSO for 5 and 10 hours

ORGANISM(S): Homo sapiens

SUBMITTER: Andrew Liss

PROVIDER: E-GEOD-55209 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment.

Huang Yinshi Y Nahar Sabikun S Nakagawa Akifumi A Fernandez-Barrena Maite G MG Mertz Jennifer A JA Bryant Barbara M BM Adams Curtis E CE Mino-Kenudson Mari M Von Alt Kate N KN Chang Kevin K Conery Andrew R AR Hatton Charlie C Sims Robert J RJ Fernandez-Zapico Martin E ME Wang Xingpeng X Lillemoe Keith D KD Fernández-Del Castillo Carlos C Warshaw Andrew L AL Thayer Sarah P SP Liss Andrew S AS

Clinical cancer research : an official journal of the American Association for Cancer Research 20160511 16

<h4>Purpose</h4>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.<h4>Experimental design</h4>In vivo pooled shRNA screens targeting 118 epigenetic proteins w ...[more]

PMID: 27169995

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Project description:Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET inhibitors and their significant activity in diverse tumor models has rapidly translated into clinical studies and has motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of bromodomain protein complexes complicates predictions of consequences of their pharmacological targeting. To address this issue we developed a promiscuous bromodomain inhibitor (bromosporine, BSP) that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle we studied the effect of BSP in leukemic cell-lines known to be sensitive to BET inhibition and found as expected strong anti-proliferative activity. Comparison of the modulation of transcriptional profiles by BSP at short inhibitor exposure resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, non-selective targeting of BRDs identified BETs, but not other BRDs, as master regulators of a context dependent primary transcription response. Cells were seeded the day prior to treatment at 2x10^5 per ml. Treatments were performed so that a final concentration of 0.1 % DMSO (Cat.#D1435; Sigma) was achieved and cells were incubated with DMSO or 500 nM test compound (BSP, JQ1, LP99, GSK2801, iCBP112 or OF1) for 6 h prior to isolation of RNA. Total RNA was isolated using a standard TRIzol (Invitrogen) protocol and prepared using RNeasy columns (Cat.#74106 plus; Qiagen). RNA was quantified using a Nanodrop spectrophotometer (model ND1000; Thermo Fisher) and integrity assessed on a BioAnalyzer (2100; Agilent Laboratories, USA). All samples had a RNA Integrity Number (RIN) â¥ 9. Biological triplicates were performed for each condition tested.

Dataset Information

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

Publications

Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment.

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