Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells.
Epigenetic abnormalities are associated with non-small cell lung cancer (NSCLC) initiation and progression. Epigenetic drugs are being studied and in clinical trials. However, the molecular mechanism underlying the apoptosis by the epigenetic agents remains unclear. SUV39H1 is an important methyl-transferase for lysine 9 on histone H3 and usually related to gene transcriptional suppression, and chaetocin acts as the inhibitor of SUV39H1. We demonstrated here that chaetocin effectively suppressed the growth of multiple lung cancer cells through inducing apoptosis in a death receptor 5 (DR5)-dependent manner. Chaetocin treatment activated endoplasmic reticulum (ER) stress which gave rise to the up-regulation of ATF3 and CHOP. Furthermore, ATF3 and CHOP contributed to the induction of DR5 and subsequent apoptosis. When SUV39H1 was silenced with siRNA, the expression of ATF3, CHOP and DR5 was elevated. Thereafter, knockdown of SUV39H1 induced apoptosis in NSCLC cells. In summary, chaetocin pharmacologically inhibits the activity of SUV39H1 which provokes ER stress and results in up-regulation of ATF3 and CHOP, leading to DR5-dependent apoptosis eventually. These findings provide a novel interpretation on the anti-neoplastic activity of epigenetic drugs as a new therapeutic approach in NSCLC.
Shandong University School of Life Sciences, Rm103, South Bldg, 27 Shanda South RD, Jinan, 250100, China.|Department of Otolaryngology Head and Neck Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, China.
Xianfang
X
Liu
Shandong University School of Life Sciences, Rm103, South Bldg, 27 Shanda South RD, Jinan, 250100, China.
Sen
S
Guo
Shandong University School of Life Sciences, Rm103, South Bldg, 27 Shanda South RD, Jinan, 250100, China.
Xiangguo
X
Liu
Shandong University School of Life Sciences, Rm103, South Bldg, 27 Shanda South RD, Jinan, 250100, China. suling@sdu.edu.cn.
Ling
L
Su
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010879:Piperazines / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D010879:Piperazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; C002511:chaetocin
ATF3; Apoptosis; CHOP; Chaetocin; DR5; SUV39H1