PT  - JOURNAL ARTICLE
AU  - Carter A. Wright
AU  - Emily R. Gordon
AU  - Sara J. Cooper
TI  - Multi-omic analysis of HDAC1 function in pancreatic cancer reveals altered GTPase activity impacting chemoresistance
AID  - 10.1101/2022.09.06.506214
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.09.06.506214
4099  - http://biorxiv.org/content/early/2022/11/23/2022.09.06.506214.short
4100  - http://biorxiv.org/content/early/2022/11/23/2022.09.06.506214.full
AB  - Background Multi-drug resistance is a key factor controlling patient outcomes in pancreatic ductal adenocarcinoma (PDAC). A mechanistic understanding of resistance enables development of novel treatments and precision medicine. Chromatin remodeling, mediated by altered expression and function of regulators including HDAC1, is one mechanism of resistance. We describe a multi-omic analysis of HDAC1, a histone deacetylase involved in several chromatin remodeling complexes, to understand how overexpression contributes to multi-drug resistance and patient survival in PDAC.Methods We overexpressed HDAC1 in MIA PaCa-2 cells using CRISPRa and characterized gene expression and HDAC1 function using RNA-sequencing and ChIP-sequencing for HDAC1 and H3K27 acetylation. Analysis of HDAC1 targets revealed altered GTPase activity, which was confirmed using a biochemical assay.Results HDAC1 overexpression in PDAC facilitates multi-drug resistance by promoting a stem-like state through global chromatin remodeling. A downstream result is increased GTPase activity which can be reversed by chemical inhibition or knockdown of HDAC1. HDAC1 target genes identified using in vitro and in vivo analysis led to the development of a clinically relevant nine-transcript prognostic signature that predicts patient prognosis.Conclusions Integrative genomic analysis demonstrates HDAC1’s role in promoting drug resistance. These findings fuel the advancement of novel strategies for treatment and precision oncology.Competing Interest StatementThe authors have declared no competing interest.