Inhibition of Histone Deacetylases Induces Cancer Cell Apoptosis Through the PERK Pathway of ER Stress Response

Activation of the endoplasmic reticulum (ER) stress is an adaptive response to disturbed ER homeostasis caused by the accumulation of misfolded or unfolded proteins, or an acute increase in the entry of newly synthesised or mutated proteins into the ER lumen. Overwhelmed or prolonged ER stress causes apoptotic cell death or a maladaptive state of the cell, resulting in various pathological diseases including cancer, inflammation and aging. With a screening of a chemical compound library, here we show that inhibition of histone deacetylases (HDACs) induces ER stress, along with increased retro-translocation of misfolded proteins from the ER lumen to the cytosol for proteasomal degradation. HDAC inhibitors (HDACi) activate the PERK-eIF2α subbranch of the unfolded protein response (UPR), whereas the IRE1α and ATF6 pathways are not affected. Inhibition of the PERK subbranch with specific siRNA or a small molecule inhibitor ameliorates HDACi-induced apoptotic cell death. In addition, a non-phosphorylatable mutant of eIF2α, a critical substrate that transduces the PERK-mediated ER stress response, abolishes apoptosis induced by HDACi, but not by the DNA damage reagent doxorubicin. HDACi reduce the sizes of tumours formed from wildtype but not eIF2α^S51A-mutant cells in a xenograft model, further demonstrating the involvement of the PERK subbranch in HDACi-induced ER stress and cell death. Our study reveals novel effects of the well-studied family of HDAC inhibitors, which can be explored further in clinics to treat certain types of cancer manifested with abnormal ER stress conditions.