Researcher's Profile

CHING-CHOW CHEN (陳青周)

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Research Outline     

CREB-binding protein (CBP) and its homologue p300 are transcriptional coactivators that mediate communication between transcription factors and the transcriptional machinery and thus appear to be important for gene transcription. We have reported the post-translational modification of p300 and CBP by Akt and IKKα respectively. Our results demonstrated that Akt phosphorylation of p300 at Ser 1834 increased its recruitment to the ICAM-1 promoter and its HAT (histone acetyltransferase) activity. IKKα phosphorylates CBP at serine 1382 and serine 1386 consequently increasing CBP’s HAT and transcriptional activities. Importantly, such phosphorylation enhances NF-κB-mediated and suppresses p53-mediated gene expression by switching the binding preference of CBP from p53 to NF-κB, thus promoting cell growth.
From the deep investigation of transcriptional coactivator, we are intrigued by histone modification and enter into the epigenetic study. Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding region. Disruption of epigenetic networks can cause several major pathologies including cancer. Several inhibitors of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) have shown promising antitumor effects. We found that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors, statins with a carboxylic acid-containing long chain inhibit HDACs. Therefore, a drug that potently inhibits both HMGR and HDACs was sought. We designed and synthesized three statin hydroxamates (JMF3086, JMF3171 and JMF3173) that directly inhibited HMGR and class I and II HDACs. These compounds effectively suppressed cell viability in numerous tumor cells, but not in normal cells. A genome-wide ChIP-on-chip analysis demonstrated that JMF3086 down-regulated the expression of inflammatory and stemness genes and up-regulated tumor suppressor genes. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) predicted that several of the inflammatory genes were regulated by NF-B and that the apoptosis-related genes were regulated by NR3C1. In mice, oral administration of these compounds prevented dextran sulfate sodium (DSS)-induced acute colitis. Moreover, the statin hydroxamates efficiently prevented and treated colitis-associated CRC induced by azoxymethane (AOM)/DSS as well as metastatic CRC. The self-renewal and stemness of colorectal cancer stem cells (CSCs) were inhibited by statin hydroxamates in vitro and in vivo. These data provided compelling evidence that statin hydroxamates are dual-targeted therapeutic agents that show significant efficacy in preclinical models, representing a novel strategy for the prevention and treatment of solid tumors.
We also demonstrate that inhibition of autophagy enhances the efficacy of statins, whereas HDACi induced autophagic cell death in cancer cells. We propose that AMPK, cytoplasmic p21, and Akt signaling are crucial determinants of cell fates (i.e. life or death) while autophagy is induced. Therefore, targeting the autophagic signaling pathways represents a new direction in the development of anticancer therapies. Recently, we also found that HDACi induced the gene expression of MHC class I-like molecule, CD1d, in solid tumors through the inhibition of HDAC1/2 and activation of Sp1. This implies that HDACi could exert anticancer effect via the modulation of immune response.

Cancer stem cells research
My lab is also interested in cancer stem cells (CSCs) and investigates epigenetic drugs to eliminate CSCs. Cancer stem cells, also called tumor-initiating cells, is a small population of cancer cells possessing the stem-like capacity that is “self-renew”, multi-lineage differentiation and proliferation. CSCs play a major role in the initiation, maintenance, and clinical outcome of cancers and are related to drug resistance, metastasis and relapse of cancers. We found that pro-survival markers of ER stress/UPR (GRP78) and autophagy (p62) were increased in HCT116-derived colonospheres. DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) down-regulated GRP78 and p62, and up-regulated a pro-apoptotic CHOP. Zeb reduced the ALDH-positive and CD44+/CD166+ populations in HCT116 cells, indicating that Zeb might selectively target CSCs of colorectal cancer cells. We also discovered JMF compounds selectively eliminated HCT116-derived colonospheres, repressed colonosphere-induced xenograft expansion, and decreased the CSCs marker in AOM/DSS-induced CRC mice model.