Targeting EZH2 for cancer therapy

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Presentation transcript:

Targeting EZH2 for cancer therapy 第六届中国肿瘤学术大会 2010.5.21，上海 Targeting EZH2 for cancer therapy Yangchao Chen, PhD Assistant Professor School of Biomedical Sciences Faculty of Medicine The Chinese University of Hong kong

Histone modification plays an important role in gene regulation Strands of DNA are wrapped around histone octamers, forming nucleosomes. These nucleosomes are organized into chromatin, the building block of a chromosome. Rodenhiser, Mann, CMAJ 174, 341 (2006)

Polycomb group (PcG) genes: A group of genes that are best known to regulate embryonic development as inhibitors of homeobox gene expression. Polycomb repression complex (PRC): PRC1: Bmi-1, Ring1, Hph, Hpc PRC2: Eed, Ezh2, Su(z)12, YY1

Sparmann and Lohuizen Nature Reviews Cancer 6, 846–856 (November 2006)

Enhancer of Zeste Homolog 2 (EZH2) A PcG gene with critic roles inembryonic development and cellular differentiation. Associated with methylation of histone H3 Lys 27 (H3K27). Genes & Development 2004 Science 2005.

EZH2 was overexpressed in hepatocellular carcinoma. Br J Cancer. 2005; 92:1754-1758

RNAi targeting EZH2 inhibited HCC tumor growth in vivo 300 600 900 1200 1500 1800 2 4 6 8 10 Tumor volume (mm 3 ) RNAi(-) RNAi(+) Chen Hepatology. 2007; 46: 200-8.

Overexpression of EZH2 alone in non-tumorigenic human hepatocyte caused tumor formation in vivo Phase contrast EGFP MIHA EZH2 EZH2ΔSET Vec Myc Actin MIHA-EZH2: 4/5 mice formed tumor (80% tumor formation).

RNAi targeting EZH2 inhibited pancreatic cancer cell growth in vitro. phase contrast EGFP B A SW1990 shScrml shEZH2 EZH2 Actin SW1990 EZH2 Actin PANC-1 shScrml shEZH2 PANC-1 C Cancer Letters, 2010

RNAi targeting EZH2 inhibited pancreatic cancer tumor growth in vivo. Cancer Letters, 2010

EZH2 plays an important role in liver metastasis of pancreatic cancer. RNAi(-) RNAi(+) Cancer Letters, 2010

EZH2 is not a target of chemotherapeutic drugs HepG2 Hep3B 5-FU CDDP Ctrl 5-FU CDDP Ctrl EZH2 Actin Dox Ctrl EZH2 Actin

Small molecule inhibitor of EZH2 selectively inhibited cancer cell growth Colon cancer Pancreatic cancer Actin EZH2 Suz12 Zp - + In collaboration with NIH

Natural product 1 inhibited EZH2 expression in cancer cells Ctrl. NP1 Ctrl. NP1 EZH2 H3K27 Actin Hep3B Bel7404 NP1: a natural compound isolated from a Traditional Chinese Medicine herb. In collaboration with IMM, PUMC

NP1 selectively inhibited HCC cell growth

NP1 induced apoptosis Ctrl NP Bel7404

Summary EZH2 represents a potential therapeutic target for cancer. 2. One natural product effectively inhibits EZH2 and tumor growth. Hepatology 2007, Proteomics 2007, Cancer Letters 2009, Proteomics 2009, Cancer Letters 2010.

Acknowledgement Rufina Li Leo Cheung Connie Chan Tian Xia School of Biomedical Sciences Prof. Joseph JY Sung Prof. Jun Yu Prof. Alfred Cheng Dept Medicine & Therapeutics Prof. HF Kung Hong Yao School of Public Health Overseas collaborators: IMM, PUMC, Beijing NIH, US

Funding Agency