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Melatonin induces apoptosis of colorectal cancer cells through HDAC 4 nuclear import mediated by C a MKII inactivation
Author(s) -
Wei JiaYi,
Li WanMing,
Zhou LinLin,
Lu QiuNan,
He Wei
Publication year - 2015
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12226
Subject(s) - melatonin , apoptosis , acetylation , histone deacetylase , cell growth , cancer research , biology , chemistry , microbiology and biotechnology , histone , endocrinology , biochemistry , gene
Abstract Melatonin induces apoptosis in many different cancer cell lines, including colorectal cancer. However, the precise mechanisms involved remain largely unresolved. In this study, we provide evidence to reveal a new mechanism by which melatonin induces apoptosis of colorectal cancer LoVo cells. Melatonin at pharmacological concentrations significantly suppressed cell proliferation and induced apoptosis in a dose‐dependent manner. The observed apoptosis was accompanied by the melatonin‐induced dephosphorylation and nuclear import of histone deacetylase 4 ( HDAC 4). Pretreatment with a HDAC 4‐specific si RNA effectively attenuated the melatonin‐induced apoptosis, indicating that nuclear localization of HDAC 4 is required for melatonin‐induced apoptosis. Moreover, constitutively active Ca 2+ /calmodulin‐dependent protein kinase II alpha ( C a MKII α ) abrogated the melatonin‐induced HDAC 4 nuclear import and apoptosis of LoVo cells. Furthermore, melatonin decreased H3 acetylation on bcl‐2 promoter, leading to a reduction of bcl‐2 expression, whereas constitutively active C a MKII α (T286D) or HDAC 4‐specific si RNA abrogated the effect of melatonin. In conclusion, the present study provides evidence that melatonin‐induced apoptosis in colorectal cancer LoVo cells largely depends on the nuclear import of HDAC 4 and subsequent H3 deacetylation via the inactivation of C a MKII α .