Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases

Nithya Kartha; Jessica E Gianopulos; Zachary Schrank; Sarah M Cavender; Stephanie Dobersch; Bryan D Kynnap; Adrianne Wallace-Povirk; Cynthia L Wladyka; Juan F Santana; Jaeseung C Kim; Angela Yu; Caroline M Bridgwater; Kathrin Fuchs; Sarah Dysinger; Aaron E Lampano; Faiyaz Notta; David H Price; Andrew C Hsieh; Sunil R Hingorani; Sita Kugel

doi:10.1126/scitranslmed.abn9674

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Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases

Journal article

Peer reviewed

Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases

Nithya Kartha, Jessica E Gianopulos, Zachary Schrank, Sarah M Cavender, Stephanie Dobersch, Bryan D Kynnap, Adrianne Wallace-Povirk, Cynthia L Wladyka, Juan F Santana, Jaeseung C Kim, …

Science translational medicine, Vol.15(694), eabn9674

05/03/2023

DOI: 10.1126/scitranslmed.abn9674

PMCID: PMC10327536

PMID: 37134154

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10327536/pdf/nihms-1899148.pdfView

Open Access

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is classified into two key subtypes, classical and basal, with basal PDAC predicting worse survival. Using in vitro drug assays, genetic manipulation experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDAC, we found that basal PDACs were uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9, and this sensitivity was recapitulated in the basal subtype of breast cancer. We showed in cell lines, PDXs, and publicly available patient datasets that basal PDAC was characterized by inactivation of the integrated stress response (ISR), which leads to a higher rate of global mRNA translation. Moreover, we identified the histone deacetylase sirtuin 6 (SIRT6) as a critical regulator of a constitutively active ISR. Using expression analysis, polysome sequencing, immunofluorescence, and cycloheximide chase experiments, we found that SIRT6 regulated protein stability by binding activating transcription factor 4 (ATF4) in nuclear speckles and protecting it from proteasomal degradation. In human PDAC cell lines and organoids as well as in murine PDAC genetically engineered mouse models where SIRT6 was deleted or down-regulated, we demonstrated that SIRT6 loss both defined the basal PDAC subtype and led to reduced ATF4 protein stability and a nonfunctional ISR, causing a marked vulnerability to CDK7 and CDK9 inhibitors. Thus, we have uncovered an important mechanism regulating a stress-induced transcriptional program that may be exploited with targeted therapies in particularly aggressive PDAC.

Animals

Carcinoma, Pancreatic Ductal - pathology

Cell Line, Tumor

Cyclin-Dependent Kinases

Humans

Mice

Pancreatic Neoplasms - pathology

Sirtuins - genetics

Sirtuins - therapeutic use

Details

Title: Subtitle: Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases
Creators: Nithya Kartha - Fred Hutch Cancer Center
Jessica E Gianopulos - Fred Hutch Cancer Center
Zachary Schrank - Fred Hutch Cancer Center
Sarah M Cavender - Fred Hutch Cancer Center
Stephanie Dobersch - Fred Hutch Cancer Center
Bryan D Kynnap - University of Iowa
Adrianne Wallace-Povirk - Fred Hutch Cancer Center
Cynthia L Wladyka - Fred Hutch Cancer Center
Juan F Santana - University of Iowa
Jaeseung C Kim - Princess Margaret Cancer Centre
Angela Yu - Fred Hutch Cancer Center
Caroline M Bridgwater - Fred Hutch Cancer Center
Kathrin Fuchs - Friedrich-Alexander-Universität Erlangen-Nürnberg
Sarah Dysinger - University of Pennsylvania
Aaron E Lampano - Fred Hutch Cancer Center
Faiyaz Notta - Princess Margaret Cancer Centre
David H Price - University of Iowa
Andrew C Hsieh - Fred Hutch Cancer Center
Sunil R Hingorani - Fred Hutch Cancer Center
Sita Kugel - Fred Hutch Cancer Center
Resource Type: Journal article
Publication Details: Science translational medicine, Vol.15(694), eabn9674
DOI: 10.1126/scitranslmed.abn9674
PMID: 37134154
PMCID: PMC10327536
NLM abbreviation: Sci Transl Med
eISSN: 1946-6242
Grant note: R37 CA241472 / NCI NIH HHS
Language: English
Date published: 05/03/2023
Academic Unit: Biology; Biochemistry and Molecular Biology
Record Identifier: 9984402860302771

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9 Times Cited - Web of Science