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Regulation of Transcriptional co-activators

Our lab demonstrated that PI3K/Akt pathway is involved in the ICAM-1 gene expression through phosphorylating p300 instead of regulating IKKb/NF-kB or p65 transcriptional activity. p300 and its homologue CREB-binding protein (CBP) are transcriptional coactivators inducing histone acetylation that mediates the communication between transcription factors and the transcriptional machinery. We presented evidence showing that p300 is phosphorylated by Akt at Ser-1834 both in vivo and in vitro. This Ser-1834 phosphorylation is critical for the transactivation of p300 by stimulating its HAT (histone acetyltransferase) activity, the assembly of transcription factors, and the recruitment of basal transcriptional machinery to the ICAM-1 promoter. We further demonstrated that nuclear IKK£\ phosphorylates CBP at serine 1382 and serine 1386 to stimulate HAT, thereby increasing its transcriptional activities. Importantly, such phosphorylation enhances NF-£eB-mediated, while suppressing p53-mediated, gene expression by switching the binding preference of CBP from p53 to NF-£eB, thus promoting cellular growth. Our discovery was highlighted in the issue of Molecular Cell (April 27, 2007) by a leading expert of this field. In addition, Faculty of 1000 also strongly recommended our paper as a must-read paper.

  Epigenetic Pharmacology and Drug Discovery

While getting deeper into the mechanisms of transcriptional coactivators, we were intrigued by histone modification and therefore have further dedicated ourselves to epigenetic studies. Disruption of epigenetic regulatory networks is known to cause diseases like cancer. Several inhibitors of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) have been shown to exert promising anticancer effects. We first demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors, statins containing carboxylic acid chain, a structure similar to the functional group of hydroxamate HDAC inhibitors TSA and SAHA, also inhibit HDACs. Based on this finding, we designed a drug that dually inhibits both HMGR and HDACs. We synthesized JMF compounds that directly inhibit HMGR and class I and II HDACs ADDIN EN.CITE  ADDIN EN.CITE.DATA  (J. Med. Chem. 2013). JMF induced apoptosis in colorectal cancer cells via a caspase-dependent pathway. It showed therapeutic efficacy against azoxymethane (AOM)/dextran sodium sulphate (DSS)-induced CRC in mice. JMF also inhibited CRC metastasis to livers or lungs and the stemness in mouse models. Furthermore, JMF potentiated the efficacy of oxaliplatin in different preclinical CRC models. Our data provide compelling evidence that dual-targeting JMF exert significant therapeutic benefits against CRC in preclinical models and are promising new drugs for CRC treatment. Various polypharmacological molecules exhibiting dual inhibition on HDACs and other therapeutic targets have been developed and provided an impetus to use hybrid technology to develop more anti-cancer treatment.

  Epigenetic Pharmacology in Lung Cancers

We also studied non-small-cell lung cancer (NSCLC) harboring EGFR activating mutation which accounts for 60% NSCLC patients in East Asia. The EGFR tyrosine kinase inhibitor (TKI) gefitinib is highly effective for these patients. However, acquired resistance can develop as soon as one year after gefitinib treatment. We discovered that down-regulation of dual specificity phosphatase (DUSP1) might be a novel mechanism underlying acquired resistance against gefitinib, and went on to synthesize a novel HDAC inhibitor (HDACi) WJ-26210-2 in combination with gefitinib, which was shown to induce DUSP1 up-regulation in resistant cells to restore gefitinib sensitivity. In addition, DUSP1 expression correlates with gefitinib sensitivity in clinical study and could serve as a predictive biomarker. Therefore, our studies provided not only mechanistic insights into gefitinib acquired resistance but also a promising strategy to overcome it.

We also found that induction of c-Cbl, an E3 ligase, could be a therapeutic strategy of lung cancer. C-Cbl expression was lost in lung tumor part compared with its adjacent normal tissue in patients¡¦ specimens. Ectopic expression of c-Cbl induced growth inhibition and apoptosis as well as EGFR down-regulation in NSCLC cells. HDACi WJ-26210-2 induced in vitro and in vivo expression of c-Cbl to exert anti-cancer effect in both wild-type and mutant EGFR NSCLC cells. c-Cbl up-regulation induced by HDACi could be a promising strategy for NSCLC treatment and is also a novel mechanism for HDACi-induced anti-cancer effect.

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1] Induction of c-Cbl contributes to anti-cancer effects of HDAC inhibitor in lung cancer. Oncotarget 6:12481-12492, 2015. [Abstract]

2] DUSP1 expression induced by HDAC1 inhibition mediates gefitinib sensitivity in non-small-cell lung cancers. Clinical Cancer Res. 21:428-438, 2015. (Highlight of January 15, 2015 issue) [Abstract]

3] Design and synthesis of dual-action inhibitors targeting histone deacetylases and HMG-CoA reductase for cancer treatment. J Med. Chem.  56:3645-3655, 2013. [Abstract] 

4] Statins increase p21 expression through inhibition of HDAC activity and release of promoter-associated HDAC1/2.  Cancer Res. 68: 2375-2383, 2008.  (highlight and cover of April, 2008 issue) [Abstract]

5] Phosphorylation of CBP by IKKa promotes cell growth by switching the binding preference of CBP from p53 to NF-kB. Molecular Cell, 26: 75-87, 2007.(F1000 and highlighted by Molecular Cell) [Abstract]

6] Akt phosphorylation of p300 at Ser-1834 is essential for its HAT and transcriptional activity. Mol. Cell. Biol . 25:6592-6602, 2005. [Abstract]

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1] Inflammation and Cancer.

2] Epigenetic regulations.

3] Regulation of transcription factors and co-activators.

4] Histone modifications and gene transcription.

5] Targeted cancer therapy

6] Autophagy and metabolism

1] PCR thermocycler

2] Isoelectric focusing system

3] RNase Protection Assay (RPA)