Changmeng Cai, PhD

About Changmeng Cai, PhD

changmeng caiDr. 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 

  1. F. Ma, H. Ye, H. H. He, S. J. Gerrin, S. Chen, B. Tanenbaum, C. Cai, A. G. Sowalsky, L. He, H. Wang, S. P. Balk, and X. Yuan. SOX9 drives WNT pathway activation in prostate cancer . J Clin Invest. 2016;126(5):1745-1758. doi:10.1172/JCI78815. Epub 2016 Apr 4.

  2. Gao S, Ye H, Gerrin S, Wang H, Sharma A, Chen S, Patnaik A, Sowalsky AG, Voznesensky O, Han W, Yu Z, Mostaghel EA, Nelson PS, Taplin ME, Balk SP, Cai C. ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer. Clin Cancer Res. 2016 Mar 2. [Epub ahead of print]PMID: 26936914

  3. Hsieh CL, Botta G, Gao S, Li T, Van Allen EM, Treacy DJ, Cai C, He HH, Sweeney C, Brown M, Balk SP, Nelson PS, Garraway L, and Kantoff PW. (2015) PLZF, a tumor suppressor genetically lost in metastatic castration resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy. Cancer Research. 75(10):1944-8.

  4. Cai C , He HH, Gao S, Chen S, Yu Z, Gao Y, Chen S, Chen MW, Zhang J, Ahmed M, Wang Y, Metzger E, Schule R, Liu XS, Brown M, and Balk SP. (2014) Lysine specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. Cell Reports. 9(5):1618-27.

  5. Chen E, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RT, Kantoff P, Montgomery B, Nelson PS, Bubley GJ, Balk SP, Taplin ME. (2015) Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors. Clin Cancer Res. 21(6): 1273-80.

  6. Yu Z, Cai C, Gao S, Nicholas IS, Shen HC, and Balk SP. (2014) Galeterone prevents androgen receptor binding to chromatin and enhances degradation of mutant androgen receptor. Clinical Cancer Research. 20(15):4075-85.

  7. Yu Z, Chen S, Sowalsky AG, Voznesensky OS, Mostaghel EA, Nelson PS, Cai C, Balk SP. (2014) Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate Cancer. Clin Cancer Res. 20(6):1590-1600.

  8. Liu F, Zhang X, Weisberg E, Chen S, Hur W, Wu H, Zhao Z, Wang W, Mao M, Cai C, Simon NI, Sanda T, Wang J, Look AT, Griffin JD, Balk SP*, Liu Q*, and Gray NS*. (2013) Discovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer. ACS Chemical Biology . 8(7):1423-1428.

  9. Yuan X, Cai C, Chen S, Chen S, Yu Z, Balk SP. (2013) Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene . Jun 10. doi: 10.1038/onc.2013.235.

  10. Chen S, Jiang X, Gewinner CA, Asara JM, Simon NI, Cai C, Cantley LC, and Balk SP. (2013) Tyrosine kinase Bmx phosphorylates Phosphotyrosine primed motif regulating multiple tyrosine kinases. Science Signaling. 6(277):ra40.

  11. Cai C , Yuan X, and Balk SP. (2013) Androgen receptor epigenetics. Translational Andrology and Urology. 2(3):148-157.

  12. Cai C * , Wang H*, He HH, Chen S, He L, Ma F, Mucci L, Wang Q, Fiore C, Sowalsky A, Loda M, Liu XS, Brown M, Balk SP, and Yuan X. (2013) ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer. The Journal of Clinical Investigation . 123(3):1109-22. PMID: 23426182

  13. Xu K, Wu JZ, Groner AC, He HH, Cai C, Lis RT, Wu X, Stack EC, Loda M, Liu T, Xu H, Cato L, Thornton JE, Gregory RI, Morrissey C, Vessella RL, Montironi R, Magi-Gulluzzi C, Kantoff PW, Balk SP, Liu XS, and Brown M. (2012) EZH2 Oncogenic Activity in Castration Resistant Prostate Cancer is Polycomb-Independent. Science. 338(6113):1465-9. PMID: 23239736

  14. Shen H, Shanmugasundaram K, Simon NI, Cai C, Wang H, Chen S, and Balk SP & Rigby A. (2012) In Silico discovery of androgen receptor antagonists with activity in castration resistant prostate cancer. Molecular Endocrinology. 26(11):1836-46. PMID: 23023563

  15. Chen S, Gulla S, Cai C, and Balk SP. (2012) Androgen receptor serine 81 phosphorylation mediates chromatin binding and transcriptional activation. The Journal of Biological Chemistry. 287(11): 8571-83. PMID: 22275373

  16. Fang Z, Zhang T, Dizeyi N, Chen S, Wang H, Swanson KD, Cai C, and Balk SP & Yuan X. (2012) Androgen receptor enhances p27 degradation in prostate cancer cells through rapid and selective TORC2 activation. The Journal of Biological Chemistry. 287(3):2090-8. PMID: 22139837

  17. Cai C *, Hsieh CL*, Gao S*, Kannan A, Bhansali M, Govardhan K, Dutta R, and Shemshedini L. (2012) Soluble guanylyl cyclase alpha1 and p53 cytoplasmic sequestration: a novel mechanism for p53 down-regulation in prostate cancer. Molecular Endocrinology. 26(2):292-307. PMID: 22174378

  18. Cai C , He HH, Chen S, Coleman I, Wang H, Fang Z, Chen S, Nelson PS, Liu XS, Brown M, and Balk SP. (2011) Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine demethylase 1. Cancer Cell. 20(4):457-71. PMID: 22014572

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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.)