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 Ph.D. 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
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
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.
Assistant Professor in Center for Personalized Cancer Therapy, Department
of Biology, University of Massachusetts Boston, Boston, MA: May
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
Postdoctoral Training: Cancer Biology, Harvard Medical School/ Beth Israel
Deaconess Medical Center: 2007-2011
Ph.D.: Molecular Biology, The University of Toledo: 2002-2007
M.S.: Bioengineering, The University of Toledo: 2000-2002
B.S.: 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
DF/HCC-Prostate Cancer SPORE Career Development Award: October 2009-June
Department of Defense Prostate Cancer Training Award: June 2009-January
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.
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
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.
, 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.
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.
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.
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.
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
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.
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.
, Yuan X, and Balk SP. (2013) Androgen receptor epigenetics. Translational Andrology and Urology.
, 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
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:
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
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
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
*, 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
, 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:
, 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
and Balk SP. (2011) Intratumoral androgen biosynthesis in prostate
cancer pathogenesis and r4sponse to therapy. Endocrine-Related Cancer. 18(5):R175-82.
, 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:
, 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
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
, 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.
, 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.
, 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
*, 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
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.
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
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.)