Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation.
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 (HDAC4). Pretreatment with a HDAC4-specific siRNA effectively attenuated the melatonin-induced apoptosis, indicating that nuclear localization of HDAC4 is required for melatonin-induced apoptosis. Moreover, constitutively active Ca(2+) /calmodulin-dependent protein kinase II alpha (CaMKIIα) abrogated the melatonin-induced HDAC4 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 CaMKIIα(T286D) or HDAC4-specific siRNA 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 HDAC4 and subsequent H3 deacetylation via the inactivation of CaMKIIα.
Department of Developmental Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Heping District, Shenyang, China; Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Heping District, Shenyang, China.
Jia-Yi
JY
Wei
Wan-Ming
WM
Li
Lin-Lin
LL
Zhou
Qiu-Nan
QN
Lu
Wei
W
He
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D012097:Repressor Proteins / Q000378:metabolism*
D012097:Repressor Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D008550:Melatonin
CaMKIIα; HDAC4; apoptosis; colorectal cancer; histone acetylation; melatonin