TMEFF2 is an epigenetic modulator that promotes androgen independent growth in castration-resistant prostate cancer cells

While the ability to detect PCa has improved significantly due to PSA screenings, the survival rate for men diagnosed with PCa has remained stagnant, and the disease remains the second leading cause of cancer related deaths in men. Most patients initially respond to androgen deprivation treatment\; however, a significant percentage of patients relapse with currently untreatable castration resistant prostate cancer (CRPC), during which the PCa cells develop the ability to grow in androgen depleted conditions. The androgen receptor (AR) plays a vital role in prostate development and homeostasis, and the deregulation of AR drives PCa tumorigenesis and progression to CRPC. Delineating molecular mechanisms that contribute to AR activity and/or PCa cell growth in androgen-depleted conditions may aid in the development of future CRPC therapies Epigenetic alterations play a critical role in differentiation during development, and aberrations in epigenetic regulation are associated with tumorigenesis and cancer progression. Two types of epigenetic modifications, DNA methylation and the methylation of multiple histone lysines, play significant roles in prostate cancer (PCa). Many histone methyltransferases (HMT) and demethylases (HDM), including the JMJD2 family of histone demethyalses, act as coregulators of AR, and many of these enzymes are implicated in CRPC. Because of this, HDMSs and HMTs have proven as attractive targets for therapeutic intervention. We have been studying TMEFF2, a protein that is regulated transcriptionally and translationally by the AR, and is overexpressed in PCa and CRPC suggesting a role in this disease. Data presented here demonstrate that TMEFF2 modulates JMJD2 controlled methyl histone marks and increases growth in androgen depleted conditions in CRPC cells. In correlation with its effect on histone methylation and growth, TMEFF2 overexpression increases resistance to the anti-growth effects of the pan-jumonji demethylase inhibitor, JIB-04, suggesting that TMEFF2 modulates growth, at least in part, by increasing jumonji demethylase activity. Additionally, TMEFF2 positively regulates PSA expression without altering AR levels in CRPC cells, indicating that TMEFF2 is a novel activator of AR. All together this data suggests a model in which TMEFF2, by modulating the activity of AR and JMJD2 enzymes, increases CRPC cell growth. Because CRPC remains to be a significant obstacle in the successful treatment of metastatic PCa, the results presented have the potential to be of therapeutic value