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Am J Transl Res 2012;4(1):14-23
Original Article
Epigenetic silencing of miR-34a in human prostate cancer cells and
tumor tissue specimens can be reversed by BR-DIM treatment
Dejuan Kong, Elisabeth Heath, Wei Chen, Michael Cher, Isaac Powell, Lance Heilbrun, Yiwei Li, Shadan Ali,
Seema Sethi, Oudai Hassan, Clara Hwang, Nilesh Gupta, Dhananjay Chitale, Wael A Sakr, Mani Menon, Fazlul H
Sarkar
Departments of Pathology, Oncology and Urology, Karmanos Cancer Institute, Wayne State University School of
Medicine, Detroit, Michigan, and Departments of Oncology, Pathology and Urology, Henry Ford Health System,
Detroit, MI, USA.
Received November 30, 2011; accepted December, 2011; Epub January 1, 2012; Published January 15, 2012
Abstract: Androgen Receptor (AR) signaling is critically important during the development and progression of
prostate cancer (PCa). The AR signaling is also important in the development of castrate resistant prostate
cancer (CRPC) where AR is functional even after androgen deprivation therapy (ADT); however, little is known
regarding the transcriptional and functional regulation of AR in PCa. Moreover, treatment options for primary PCa
for preventing the occurrence of CRPC is limited; therefore, novel strategy for direct inactivation of AR is urgently
needed. In this study, we found loss of miR-34a, which targets AR, in PCa tissue specimens, especially in
patients with higher Gleason grade tumors, consistent with increased expression of AR. Forced over-expression
of miR-34a in PCa cell lines led to decreased expression of AR and prostate specific antigen (PSA) as well as the
expression of Notch-1, another important target of miR-34a. Most importantly, BR-DIM intervention in PCa patients
prior to radical prostatectomy showed re-expression of miR-34a, which was consistent with decreased
expression of AR, PSA and Notch-1 in PCa tissue specimens. Moreover, BR-DIM intervention led to nuclear
exclusion both in PCa cell lines and in tumor tissues. PCa cells treated with BR-DIM and 5-aza-dC resulted in the
demethylation of miR-34a promoter concomitant with inhibition of AR and PSA expression in LNCaP and C4-2B
cells. These results suggest, for the first time, epigenetic silencing of miR-34a in PCa, which could be reversed
by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa.
(AJTR1111004).
Keywords: BR-DIM, miR-34a, androgen receptor (AR), PSA, methylation
Full Text PDF
Address all correspondence to:
Dr. Fazlul H. Sarkar
Departments of Pathology and Oncology
Karmanos Cancer Institute
Wayne State University School of Medicine
740 Hudson Webber Cancer Research Center Building
4100 JohnR Street, Detroit, MI 48201, USA.
Phone: 313-576-8327; Fax: 313-576-8389
Email: fsarkar@med.wayne.edu
Original Article
Epigenetic silencing of miR-34a in human prostate cancer cells and
tumor tissue specimens can be reversed by BR-DIM treatment
Dejuan Kong, Elisabeth Heath, Wei Chen, Michael Cher, Isaac Powell, Lance Heilbrun, Yiwei Li, Shadan Ali,
Seema Sethi, Oudai Hassan, Clara Hwang, Nilesh Gupta, Dhananjay Chitale, Wael A Sakr, Mani Menon, Fazlul H
Sarkar
Departments of Pathology, Oncology and Urology, Karmanos Cancer Institute, Wayne State University School of
Medicine, Detroit, Michigan, and Departments of Oncology, Pathology and Urology, Henry Ford Health System,
Detroit, MI, USA.
Received November 30, 2011; accepted December, 2011; Epub January 1, 2012; Published January 15, 2012
Abstract: Androgen Receptor (AR) signaling is critically important during the development and progression of
prostate cancer (PCa). The AR signaling is also important in the development of castrate resistant prostate
cancer (CRPC) where AR is functional even after androgen deprivation therapy (ADT); however, little is known
regarding the transcriptional and functional regulation of AR in PCa. Moreover, treatment options for primary PCa
for preventing the occurrence of CRPC is limited; therefore, novel strategy for direct inactivation of AR is urgently
needed. In this study, we found loss of miR-34a, which targets AR, in PCa tissue specimens, especially in
patients with higher Gleason grade tumors, consistent with increased expression of AR. Forced over-expression
of miR-34a in PCa cell lines led to decreased expression of AR and prostate specific antigen (PSA) as well as the
expression of Notch-1, another important target of miR-34a. Most importantly, BR-DIM intervention in PCa patients
prior to radical prostatectomy showed re-expression of miR-34a, which was consistent with decreased
expression of AR, PSA and Notch-1 in PCa tissue specimens. Moreover, BR-DIM intervention led to nuclear
exclusion both in PCa cell lines and in tumor tissues. PCa cells treated with BR-DIM and 5-aza-dC resulted in the
demethylation of miR-34a promoter concomitant with inhibition of AR and PSA expression in LNCaP and C4-2B
cells. These results suggest, for the first time, epigenetic silencing of miR-34a in PCa, which could be reversed
by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa.
(AJTR1111004).
Keywords: BR-DIM, miR-34a, androgen receptor (AR), PSA, methylation
Full Text PDF
Address all correspondence to:
Dr. Fazlul H. Sarkar
Departments of Pathology and Oncology
Karmanos Cancer Institute
Wayne State University School of Medicine
740 Hudson Webber Cancer Research Center Building
4100 JohnR Street, Detroit, MI 48201, USA.
Phone: 313-576-8327; Fax: 313-576-8389
Email: fsarkar@med.wayne.edu
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