Changmeng Cai, PhD
About Changmeng Cai, PhD
Dr. Cai's research is focusing on understanding the biology and function of androgens and its receptor (androgen receptor, AR) in prostate cancer (PCa) cells and targeting AR for PCa prevention and treatment of castration resistant prostate cancer (CRPC). For his PhD project, he initially focused on studying AR regulated genes and the cross talk of AR and other transcription factors such as Jun/Fos and Ets genes. His major contribution is the identification of several important AR regulated genes, including soluble guanylyl cylase and ETV1 involved in PCa cell growth and invasion. He continued on studying the function of critical AR targets in his postdoc study, particularly on fusion gene TMPRSS2-ERG. Using tissue microarray and xenograft model, he demonstrated that the expression of this fusion is restored and still AR-dependent in CRPC. In a study of TMPRSS2-ERG function, he found that ERG protein functions as a pioneer factor that redirects AR to transactivate a series of genes including SOX9, and identified SOX9 as a major downstream effector of ERG in fusion positive PCa.
His recent studies strongly suggest that intratumoral de novo androgen synthesis plays an important role for restoring AR-regulated gene expression in CRPC and developing resistance to CYP17 inhibitor treatments. Moreover, although the tissue sample availably is still limited, he has started to study the mechanisms that drive the tumor resistance to this treatment and demonstrated the role of AR variants in this progression of cancer.
His current K99 award is based on his discovery that AR can function directly as a transcriptional repressor on a subset of genes including AR, AKR1C3 (an androgen synthetic gene), and a subset of DNA synthesis/repair genes. Therefore, he proposes that the partial restoration of AR activity in CRPC cells provides a strong growth advantage by stimulating cellular metabolism without downregulation of AR repressed genes that enhance cellular proliferation. The distinct mechanisms of AR action on enhancer versus suppressor elements may make it possible to selectively augment AR transcriptional repressor function and thereby prevent or delay the emergence of CRPC.
While AR has been well established as a transcriptional activator, it was not known to function directly as a transcriptional repressor. Mechanistically, he showed that AR-mediated suppression activity requires LSD1 and its activity on demethylating mono- and di-methylated H3K4. In a follow-up study of LSD1, he has clearly demonstrated that LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Based on these results, LSD1 is a very promising therapeutic target in PCa, and particularly in CRPC, where AR activity persists and its function may be altered by epigenetic mechanisms.
Positions
Assistant Professor in Center for Personalized Cancer Therapy, Department of Biology, University of Massachusetts Boston, Boston, MA: May 2015-present
Assistant Professor in the Department of Medicine, Beth Israel Deaconess Medical Center /Harvard Medical School, Boston, MA: 2014-May 2015
Instructor in Medicine, Beth Israel Deaconess Medical Center/ Harvard Medical School, Boston, MA: October 2011-2014
Committee advisor on Master research of Patrick C. Ng (Northeastern University), Thesis title: The development of a versatile and expeditious route to PET imaging ligands and its potential applications to prostate cancer treatment and diagnosis: June 2009-May 2010
Research Fellow, Beth Israel Deaconess Medical Center/ Harvard Medical School, Boston, MA: June 2007-September 2011
Graduate Assistantship, University of Toledo, Toledo, OH: August 2000-May 2007
Education
Postdoctoral Training: Cancer Biology, Harvard Medical School/ Beth Israel Deaconess Medical Center: 2007-2011
PhD: Molecular Biology, The University of Toledo: 2002-2007
MS: Bioengineering, The University of Toledo: 2000-2002
BS: Biomedical Engineering, Tsinghua University (China): 1995-2000
Grants and Awards
NIH Pathway to Independence Award (K99/R00): October 2012-August 2017
Harvard Chinese Life Science Annual Distinguished Research Award: April 2012
DF/HCC-Prostate Cancer SPORE Career Development Award: October 2009-June 2011
Department of Defense Prostate Cancer Training Award: June 2009-January 2011
Publications
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Cai C , Chen S, Ng P, Mostaghel EA, Marck B, Matsumoto AM, Simon, NI, Wang H, Chen S, and Balk SP. (2011) Intratumoral de novo steroid synthesis activates androgen receptor in castration resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Research. 71(20):6503-13. PMID: 21868758
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Cai C and Balk SP. (2011) Intratumoral androgen biosynthesis in prostate cancer pathogenesis and r4sponse to therapy. Endocrine-Related Cancer. 18(5):R175-82. PMID: 21712345
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Cai C , Wang H, Xu Y, Chen SY, and Balk SP. (2009) Reactivation of androgen receptor regulated TMPRSS2;ERG gene expression in castration resistant prostate cancer. Cancer Research. 69(15):6027-32. PMID: 1958427
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Cai C , Portnoy CD, Wang H, Jing X, Chen SY, and Balk SP. (2009) Androgen receptor expression in prostate cancer is suppressed by activation of EGFR and ErbB2. Cancer Research. 69(12):5186-93. PMID: 19491261
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Hsieh CL*, Cai C*, Giwa A, Bivins A, Chen SY, Sabry D, Govardhan K, and Shemshedini L. (2008) Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells. Journal of Molecular Endocrinology. 41(1):11-23. PMID: 18469090
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Cai C , Hsieh CL, Omwancha J, Zheng Z, Chen SY, Baert JL, and Shemshedini L. (2007) ETV1 is a novel androgen regulated gene that mediates prostate cancer cell invasion. Molecular Endocrinology. 21(8):1835-46. PMID: 17505060
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Cai C , Hsieh CL, and Shemshedini L. (2007) c-Jun has multiple enhancing activities in the novel cross-talk between the androgen receptor and Ets variant gene 1 in prostate cancer. Molecular Cancer Research. 5(7):725-35. PMID: 17634427
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Cai C , Chen SY, Zheng Z, Omwancha J, Lin MF, Balk S, and Shemshedini L. (2007) Androgen regulation of soluble guanylyl cyclase a1 mediates prostate cancer cell proliferation. Oncogene. 26(11):1606-15. PMID: 16964290
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Cai C *, Omwancha J*, Hsieh CL, and Shemshedini L. (2007) Androgen induces expression of multidrug resistance protein gene MRP4 in prostate cancer cells. Prostate Cancer and Prostatic Diseases. 10(1):39-45. (*Equal contributions) PMID: 17003774
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Chen SY*, Cai C*, Fisher CJ, Zheng Z, Omwancha J, Hsieh CL, Shemshedini L. (2006) c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation. Oncogene. 25(54):7212-23. PMID: 16732317
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Zheng Z, Cai C, Omwancha J, Chen SY, Baslan T, Shemshedini L. (2006) SUMO-3 enhances androgen receptor transcriptional activity through a sumoylation-independent mechanism in prostate cancer cells . The Journal of Biological Chemistry. 281(7):4002-12. PMID: 16361251
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Omwancha J, Zhou XF, Chen SY, Baslan T, Fisher CJ, Zheng Z, Cai C, Shemshedini L. (2006) Makorin RING finger protein 1 (MKRN1) has negative and positive effects on RNA polymerase II-dependent transcription. Endocrine. 29(2):363-73. PMID: 16785614
(* The authors contributed equally.)