KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer

Wenyu Wang; Gokce Oguz; Puay Leng Lee; Yi Bao; Panpan Wang; Mikkel Green Terp; Henrik J Ditzel; Qiang Yu

doi:10.1084/jem.20180439

KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer

J Exp Med. 2018 Nov 5;215(11):2833-2849. doi: 10.1084/jem.20180439. Epub 2018 Sep 28.

Authors

Wenyu Wang¹, Gokce Oguz^{1

2}, Puay Leng Lee¹, Yi Bao¹, Panpan Wang³, Mikkel Green Terp⁴, Henrik J Ditzel^{4

5}, Qiang Yu^{6

2

7}

Affiliations

¹ Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore.
² Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Cancer Research Institute and School of Pharmacy, Jinan University, Guangzhou, China.
⁴ Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
⁵ Department of Oncology, Odense University Hospital, Odense, Denmark.
⁶ Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore [email protected].
⁷ Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School of Singapore, Singapore.

Abstract

PTEN deficiency in breast cancer leads to resistance to PI3K-AKT inhibitor treatment despite aberrant activation of this signaling pathway. Here, we report that genetic depletion or small molecule inhibition of KDM4B histone demethylase activates the unfolded protein response (UPR) pathway and results in preferential apoptosis in PTEN-deficient triple-negative breast cancers (TNBCs). Intriguingly, this function of KDM4B on UPR requires its demethylase activity but is independent of its canonical role in histone modification, and acts through its cytoplasmic interaction with eIF2α, a crucial component of UPR signaling, resulting in reduced phosphorylation of this component. Targeting KDM4B in combination with PI3K inhibition induces further activation of UPR, leading to robust synergy in apoptosis. These findings identify KDM4B as a therapeutic vulnerability in PTEN-deficient TNBC that otherwise would be resistant to PI3K inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / genetics
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Enzyme Inhibitors / pharmacology*
Eukaryotic Initiation Factor-2 / genetics
Eukaryotic Initiation Factor-2 / metabolism
Female
Humans
Jumonji Domain-Containing Histone Demethylases / genetics
Jumonji Domain-Containing Histone Demethylases / metabolism*
Mice
Mice, Inbred NOD
Mice, SCID
PTEN Phosphohydrolase / deficiency*
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / drug effects*
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / pathology
Unfolded Protein Response / drug effects*
Unfolded Protein Response / genetics
Xenograft Model Antitumor Assays

Substances

Enzyme Inhibitors
Eukaryotic Initiation Factor-2
Phosphoinositide-3 Kinase Inhibitors
Jumonji Domain-Containing Histone Demethylases
KDM4B protein, human
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human