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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 si RNA effectively attenuated the melatonin-induced apoptosis, indicating that nuclear localization of HDAC4 is required for melatonin-induced apoptosis. Moreover, constitutively active Ca2+/calmodulin-dependent protein kinase II alpha ( Ca MKII α) 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 Ca MKII α(T286D) or HDAC4-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 HDAC4 and subsequent H3 deacetylation via the inactivation of Ca MKII α. [ABSTRACT FROM AUTHOR]

Histone deacetylase 5 (HDAC5) undergoes signal-dependent shuttling between the nucleus and cytoplasm, which is regulated in part by calcium/calmodulin-dependent kinase (CaMK)-mediated phosphorylation. Here, we report that HDAC5 regulates the survival of cortical neurons in pathological conditions. HDAC5 was evenly localized to the nucleus and cytoplasm in cultured cortical neurons. However, in response to 50 μM NMDA conditions that induced neuronal cell apoptosis, nuclear-distributed HDAC5 was rapidly phosphorylated and translocated into cytoplasm of the cultured cortical neurons. Treatment with a CaMKII inhibitor KN93 suppressed HDAC5 phosphorylation and nuclear translocation induced by NMDA, whereas constitutively active CaMKIIα (T286D) stimulated HDAC5 nuclear export. Importantly, we showed that ectopic expression of nuclear-localized HDAC5 in cortical neurons suppressed NMDA-induced apoptosis. Finally, inactivation of HDAC5 by treatment with the class II-specific HDAC inhibitor trichostatin A (TSA) promoted NMDA-induced neuronal cell apoptosis. Altogether, these data identify HDAC5 and its intracellular translocation as key effectors of multiple pathways that regulate neuronal cell apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have shown that apoptosis can be mediated by activation of either calmodulin kinase II (CaMKII) or mitogen-activated protein kinase (MAPK), ERK and p38. In the present study, we investigated whether CaMKII is involved in activation of ERK and p38 in response to all-trans retinoic acid (ATRA) treatment in PC12 cells. Results showed that ATRA-induced activation of ERK and p38 occurred later than that of CAMKII. Knockdown of CAMKII by siRNA significantly suppressed ATRA-induced activation of ERK and p38. These results demonstrated that activation of ERK and p38 following ATRA exposure is CAMKII-dependent. Treatment with ATRA also resulted in cell death characterized by apoptosis in PC12 cells. Results suggest that CaMKII-dependent activation of ERK and p38 is related to apoptotic cell death. [Copyright &y& Elsevier]