The Mechanisms of HDAC Inhibitor-mediated G2/M Arrest:The Crosstalk between HDAC and MAPK-ERK pathway

• Main Authors: Lai, Xiang ME, 賴享玫
• Other Authors: Sun, Guang Huan
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/07546723532029853170

碩士 === 國防醫學院 === 生物及解剖學研究所 === 97 === Histone deacetylases (HDAC) are responsible for deacetylating histones and non-histone proteins, regulating gene transcription, protein function and stability. Aberrant expression and increased activity of HDACs are observed in many cancer types. Therefore histone deacetylase inhibitors (HDACi) have been introduced into preclinical studies and clinical trials to investigate their anticancer activity. There are varieties of HDACi derived from natural sources or synthetic compounds under development. LBH589 belonged to hydroxmate group HDACi posesses potent anti-cancer activity and now enters into phase II/III clinical trials with hematologic and solid cancers. In previous studies, HDACi treatment resulted in growth arrest, differentiation, and apoptosis of cancer cells. Some studies demonstrate that HDACi treatment resulted in elevation of p21 contributing to G1 cell-cycle arrest. Although less common, HDACi also induced G2/M cell-cycle arrest of cancer cells. However, the molecular mechanism involved in G2/M arrest remains unclear. In our previous study, we found that LBH589 can induce G2/M cell-cycle arrest in various cancer cell lines including renal cancer cells and prostate cancer cells. We also demonstrated that HDACi treatment resulted in G2/M arrest through degradation of aurora kinases A and B by inhibition of HDAC3 and HDAC6. However, HDACi-mediated early M phase arrest can be observed in some cell lines such as LNCaP, 293T without downregulation of aurora kinase levels. We hypothesize that there may be two distinct aurora kinase dependent and independent pathways responsible for HDACi-mediated G2/M cell-cycle arrest in cancer cells, respectively. Our results showed that HDACi treatment resulted in activating ERK activity in aurora-independent but not in aurora-dependent cancer cells with early M phase arrest. Although ERK downstream phosphatase, CDC25C, is increased its phosphorylated signal, we observed that CDC2 remain inhibitor signal at the same time. After LBH589 treatment, ERK1/2 Activity sustainability and CDC2 inactivation result in arresting at prophase. According to previous studies, we knew that HDACs interact with protein phosphatases to reflect different biological stimulation. Interestingly, protein phosphates involve ERK1/2 cascade pathway or regulate CDC25C. We consider that a series of cell cycle temporal consequences occurring depend on HDACs/protein phosphates complexes control.