HOXB13-mediated suppression of p21WAF1/CIP1 regulates JNK/c-Jun signaling in prostate cancer cells

Abstract

Many prostate cancer (PCA) patients die of recurrent disease due to the emergence of hormone-independent cancer cells of which the mechanism is not fully understood. Our previous studies demonstrated that most castrationresistant prostate cancers (CRPC) overexpress the HOXB13 transcription factor to confer positive growth signals. Since HOXB13 also suppresses p21WAF1/CIP1 (p21) expression, we studied the correlation between HOXB13 and p21 in selected samples of PCA. While there was no statistically significant correlation between expression of HOXB13 and p21, HOXB13-deficient tumors had three times higher odds for expressing p21 than HOXB13-positive tumors. Moreover, CRPC showed more negative correlation than hormone-dependent PCA (HDPC). Further in vitro proliferation assay demonstrated that androgen did not affect the growth-suppressive function of p21 in androgen-dependent PCA cells, suggesting that p21 seems to override the growthpromoting function of androgen and suppression of p21 expression by HOXB13 is an important step in PCA cell survival under no androgen influence. HOXB13 also inhibited AP-1 signals via suppressed expression of JNK/c-Jun. While HOXB13 suppressed p21 expression via regulation of JNK signals, alteration of p21 expression also affected c-Jun and AP-1 activity. Taken together, overexpression of HOXB13 in CRPC is an important step in avoiDing the growth-suppressive effect of p21 in a harsh condition such as an androgen-deprived environment.