Histone deacetylase inhibitors induce autophagy through FOXO1-dependent pathways.
Autophagy is a catabolic process in response to starvation or other stress conditions to sustain cellular homeostasis. At present, histone deacetylase inhibitors (HDACIs) are known to induce autophagy in cells through inhibition of mechanistic target of rapamycin (MTOR) pathway. FOXO1, an important transcription factor regulated by AKT, is also known to play a role in autophagy induction. At present, the role of FOXO1 in the HDACIs-induced autophagy has not been reported. In this study, we first observed that HDACIs increased the expression of FOXO1 at the mRNA and protein level. Second, we found that FOXO1 transcriptional activity was enhanced by HDACIs, as evidenced by increased FOXO1 nuclear accumulation and transcriptional activity. Third, suppression of FOXO1 function by siRNA knockdown or by a chemical inhibitor markedly blocked HDACIs-induced autophagy. Moreover, we found that FOXO1-mediated autophagy is achieved via its transcriptional activation, leading to a dual effect on autophagy induction: (i) enhanced expression of autophagy-related (ATG) genes, and (ii) suppression of MTOR via transcription of the SESN3 (sestrin 3) gene. Finally, we found that inhibition of autophagy markedly enhanced HDACIs-mediated cell death, indicating that autophagy serves as an important cell survival mechanism. Taken together, our studies reveal a novel function of FOXO1 in HDACIs-mediated autophagy in human cancer cells and thus support the development of a novel therapeutic strategy by combining HDACIs and autophagy inhibitors in cancer therapy.
a Department of Physiology ; Yong Loo Lin School of Medicine; National University of Singapore ; Singapore.
Jianbin
J
Zhang
Shukie
S
Ng
Jigang
J
Wang
Jing
J
Zhou
Shi-Hao
SH
Tan
Naidi
N
Yang
Qingsong
Q
Lin
Dajing
D
Xia
Han-Ming
HM
Shen
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
ATG, autophagy-related; BAF, bafilomycin A1; CQ, chloroquine; FOXO, forkhead box O; FOXO1; GFP, green fluorescent protein; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MEF, mouse embryonic fibroblast; MTOR; MTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; SAHA, suberoylanilide hydroxamic acid; TSA, trichostatin A; TSC, tuberous sclerosis; autophagy; cancer; cell death; histone deacetylase inhibitors; siRNA, short interfering RNA