1. Targeting EZH2 for cancer therapy
第六届中国肿瘤学术大会 ，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

2. 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)

3. 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

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

5. 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.

6. EZH2 was overexpressed in hepatocellular carcinoma.
Br J Cancer. 2005; 92:

7. 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:

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).

9. 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

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

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

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

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

14. 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

15. NP1 selectively inhibited HCC cell growth

16. NP1 induced apoptosis
Ctrl NP
Bel7404

17. 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.

18. 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

19. Funding Agency