| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 99 === The effects of histone deacetylase (HDAC) inhibitor on the expression of ADAMTS1 and EGFR were investigated in this study. In recent years, HDAC inhibitors are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies. HDAC inhibition accumulates acetylated nuclear histones and loosens the compact chromatin structure to reactivate the silenced tumour-suppressor genes. HDAC inhibitors arrest cell cycle and trigger apoptosis by induction of p21 and death-receptor-mediated extrinsic apoptotic pathways. However, their effects on cancer progression, such as angiogenesis and metastasis, are largely unexplored. The first part of this study demonstrates that pan-HDAC inhibitors, TSA and SAHA, were capable to upregulate the angio-inhibitory ADAMTS1 which was originally silenced in non-small-cell lung cancer. We also demonstrated that specific inhibition or knockdown of HDAC6 led to higher expression of ADAMTS1. We further identify the proximal SP1 binding sites were essential for the TSA-induced ADAMTS1 expression and showed that TSA dispersed the HDAC6 and SP1 and recruited the CBP to the ADAMTS1 promoter.
Expression of the epidermal growth factor receptor (EGFR) is highly correlated with metastasis and recurrence of colorectal cancer (CRC). The clinical strategy is suppressing EGF signaling by EGFR monoclonal antibodies. However, most patients are irresponsive to these antibodies due to the KRAS mutation, which constitutively activates the downstream survival signals bypassing EGFR. Histone deacetylase has also been reported to be overexpressed in colorectal cancer and correlates with poor prognosis. This study demonstrates that HDACi effectively reduced the viability of KRAS wild type and mutant cells in comparison with EGFR antibody, indicating their broad and effective antitumor effect. HDACi were capable to block the EGF signaling via silencing the EGFR expression and concurrent destabilized an active glucose transporter, SGLT1. Furthermore, we demonstrated that the class I HDACs was essential for EGFR gene transcription and a positive correlation between the expression of EGFR and HDAC3 in the specimens of colon cancer patients was also observed. More in-depth, we showed that the binding of SP1 to EGFR promoter and the accompanied recruitment of HDAC3 and CBP are essential for EGFR expression.
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