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Series GSE142046 Query DataSets for GSE142046
Status Public on May 06, 2020
Title SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Oncogenic KRAS signaling is a hallmark of pancreatic ductal adenocarcinoma (PDAC), a lethal malignancy with few treatment options. A major roadblock in deploying therapies targeting the KRAS-MAPK pathway is the rapid emergence of resistant cancer cells. However, molecular mechanisms underlying adaptive targeted therapy resistance in PDAC are poorly understood. Here we find SETD5 (SET domain containing 5) as a major epigenetic driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is identified in a genetic screen of annotated methyltransferases that mediate MEKi toxicity in PDAC cells. SETD5 expression is induced upon PDAC cells and tumors acquring MEKi-resistance and SETD5 deletion restores vulnerability of refractory PDAC to MEKi therapy in mouse models and patient-derived xenografts (PDX). SETD5 lacks intrinsic histone methyltransferase activity and rather scaffolds a distinct corepressor complex that regulates HDAC3 and G9a catalytic behaviors to couple selective deacetylation with methylation of histone H3 at lysine 9 (H3K9). Gene silencing by the SETD5 complex regulates a network of known drug resistance pathways to reprogram cellular responses to MEKi, a resistance program disrupted by G9a and HDAC3 blockade. Combinatorial pharmacological targeting of MEK1/2, G9a, and HDAC3 results in sustained tumor growth inhibition in murine and human models of PDAC. Together, our work uncovers SETD5 as a master epigenetic regulator of acquired MAPK-pathway therapy resistance and suggests an efficacious clinical path for MEKi in PDAC.
 
Overall design mRNA profiles of KPCR cells (n = 3) (sgControl + Trametinib 0.2µM, sgSETD5 + Trametinib 0.2µM, or DMSO + Trametinib 0.2µM, UNC0638 0.6 µM + RGFP966 0.6µM + Trametinib 0.2µM).
 
Contributor(s) Gozani O, Lyu R, Wang Z
Citation(s) 32442403
Submission date Dec 14, 2019
Last update date Aug 05, 2020
Contact name Or Gozani
E-mail(s) ogozani@stanford.edu
Phone (650) 736-7639
Organization name Stanford University
Department Department of Biology
Lab Or Gozani
Street address 371 Serra Mall, Room 208A Stanford, CA 94305-5020
City stanford city
State/province California
ZIP/Postal code 94305-5020
Country USA
 
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (12)
GSM4218175 DMSO_Trametinib02uM.RNA-seq.rep1
GSM4218176 DMSO_Trametinib02uM.RNA-seq.rep2
GSM4218177 DMSO_Trametinib02uM.RNA-seq.rep3
Relations
BioProject PRJNA595697
SRA SRP237633

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE142046_RAW.tar 1.3 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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