Dataset Information

CHD1_RIME - CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis

ABSTRACT: Crosslinked chromatin bound protein complexes were immunopurified, digested, and analyzed by mass spectrometry to identify and quantify proteins associate with the chromodomain helicase (Chd1).

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Noah Dephoure

LAB HEAD: Noah Dephoure

PROVIDER: PXD010468 | Pride | 2019-08-13

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	2014-02-04_REVuniprot_HUMAN_02_2014_contam_sorted.fasta	Fasta
	222995_MA_CHDIP_f03560.mzid.gz	Mzid
	222996_MA_H3K4IP_f03563.mzid.gz	Mzid
	222997_MA_IgGIP_f03558.mzid.gz	Mzid
	225806_MA_IgG_IP_050516_f03824.mzid.gz	Mzid

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Publications

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.

Augello Michael A MA Liu Deli D Deonarine Lesa D LD Robinson Brian D BD Huang Dennis D Stelloo Suzan S Blattner Mirjam M Doane Ashley S AS Wong Elissa W P EWP Chen Yu Y Rubin Mark A MA Beltran Himisha H Elemento Olivier O Bergman Andries M AM Zwart Wilbert W Sboner Andrea A Dephoure Noah N Barbieri Christopher E CE

Cancer cell 20190328 4

Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor ...[more]

PMID: 30930119

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Project description:Purpose: The goal of this study is to identify genome-wide changes in AR chromatin binding that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. ChIP-seq comparing AR chromatin binding in shControl, shMAP3K7(TAK1), shCHD1, and both (shMAP3K7/shCHD1) was used to identify AR cistrome changes resulting from loss of each of these genes. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.