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Up-Regulation of TWIST in Prostate Cancer and Its Implication as a Therapeutic Target

Departments of ¹ Anatomy and ² Pathology, Faculty of Medicine, The University of Hong Kong; ³ Department of Anatomy, The Chinese University of Hong Kong, Hong Kong, SAR, China; and ⁴ Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California

Requests for reprints: Xianghong Wang or Yong-Chuan Wong, Department of Anatomy, Laboratory Block Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China. Phone: 852-2819-2867; Fax: 852-2817-0857; E-mail: xhwang{at}hkucc.hku.hk or ycwong{at}hkucc.hku.hk.

Androgen-independent metastatic prostate cancer is the main obstacle in the treatment of this cancer. Unlike a majority of solid cancers, prostate cancer usually shows poor response to chemotherapeutic drugs. In this study, we have shown a potential novel target, TWIST, a highly conserved bHLH transcription factor, in the treatment of prostate cancer. Using malignant and nonmalignant prostate tissues, we found that TWIST expression was highly expressed in the majority (90%) of prostate cancer tissues but only in a small percentage (6.7%) of benign prostate hyperplasia. In addition, the TWIST expression levels were positively correlated with Gleason grading and metastasis, indicating its role in the development and progression of prostate cancer. Furthermore, down-regulation of TWIST through small interfering RNA in androgen-independent prostate cancer cell lines, DU145 and PC3, resulted in increased sensitivity to the anticancer drug taxol-induced cell death which was associated with decreased Bcl/Bax ratio, leading to activation of the apoptosis pathway. More importantly, inactivation of TWIST suppressed migration and invasion abilities of androgen-independent prostate cancer cells, which was correlated with induction of E-cadherin expression as well as morphologic and molecular changes associated with mesenchymal to epithelial transition. These results were further confirmed on the androgen-dependent LNCaP cells ectopically expressing the TWIST protein. Our results have identified TWIST as a critical regulator of prostate cancer cell growth and suggest a potential therapeutic approach to inhibit the growth and metastasis of androgen-independent prostate cancer through inactivation of the TWIST gene.

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