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

Abstract

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. (Cancer Res 2005; 65(12): 5153-62)

The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis

“…TWIST also enhances AKT2 expression, inhib-its p53 function and cell apoptosis, mediates HIF-1α-enhanced cancer progression, promotes cell survival, and contributes to oncogenesis, angiogenesis and acquired Taxol resistance [7,[10][11][12][13][14]. In agreement with these critical roles in cancer cells, TWIST is overexpressed in breast, gastric, hepatocellular, prostate and bladder cancers, and its upregulation correlates with low E-cadherin expression, high cancer aggressiveness and poor survival rate [3,8,[15][16][17][18][19]. These studies clearly demonstrate that TWIST is a master transcription factor that controls EMT, cancer progression and metastasis and a useful molecular target for treatment of cancer metastasis.…”

“…During early embryonic development, TWIST is required for mesoderm induction [6]. In the process of metastasis, TWIST represses E-cadherin and β-catenin expression, promotes EMT, cell motility and invasiveness, and permits the intravasation of tumor cells [3,[7][8][9]. TWIST also enhances AKT2 expression, inhib-its p53 function and cell apoptosis, mediates HIF-1α-enhanced cancer progression, promotes cell survival, and contributes to oncogenesis, angiogenesis and acquired Taxol resistance [7,[10][11][12][13][14].…”

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

“…NKX3-1 expression was stimulated 10-fold by R1881 and 3-7-fold by the other ligands ( Figure 5). TWIST1, a bHLH transcription factor that is upregulated in prostate cancer (Kwok et al, 2005), was upregulated 1.9-4.3-fold at 24 h by the other ligands. ELL2 is an RNA polymerase II elongation factor (Shilatifard et al, 1997), which interacts with the transcription factor EAF2 (ELL associated factor 2) (Simone et al, 2003).…”

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

“…Elevated Twist-1 expression is correlated with a poor prognosis and high risk of metastasis in breast, prostate, ovarian, cervical and many others human cancers (Elias et al, 2005;Kwok et al, 2005;Mironchik et al, 2005;Kyo et al, 2006;Puisieux et al, 2006;Hosono et al, 2007;Shibata et al, 2008). Recent reports suggest that high levels of Twist-1 confer cancer cells resistance to various chemotherapeutic drugs (Pham et al, 2007;Zhang et al, 2007;Shiota et al, 2008).…”