Article open access publication

KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancerKDM4B is a therapeutic target in PTEN-lost TNBC

Journal of Experimental Medicine, Rockefeller University Press, ISSN 0022-1007

Volume 215, 11, 2018

DOI:10.1084/jem.20180439, Dimensions: pub.1107293550, PMC: PMC6219741, PMID: 30266800,



  1. (1) Genome Institute of Singapore, grid.418377.e
  2. (2) National University of Singapore, grid.4280.e
  3. (3) Jinan University, grid.258164.c
  4. (4) University of Southern Denmark, grid.10825.3e, SDU
  5. (5) Odense University Hospital, grid.7143.1, Southern Denmark Region
  6. (6) Duke NUS Graduate Medical School, grid.428397.3









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.


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