Castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) are major challenges in prostate cancer (PCa) therapy. Activation of the androgen receptor (AR) pathway is the main mechanism underlying CRPC progression. Development of NEPC is also associated with castration resistance, and one of known drivers of NEPC is N-Myc oncoprotein. We have found that the histone demethylase JMJD1A is upregulated in CRPC and NEPC tissues; JMJD1A supports growth of CRPC cells by promoting AR activity and c-Myc levels, while it supports NEPC cell growth by increasing N-Myc levels. However, selective inhibitors of JMJD1A are not yet available. We have identified a new pathway that regulates JMJD1A stability and chromatin recruitment. Our preliminary data shows that JMJD1A is targeted for ubiquitination and consequent degradation by the ubiquitin ligase STUB1, whereas JMJD1A acetylated by acetyltransferase p300 escapes STUB-induced degradation. We observed elevation of JMJD1A acetylation levels in enzalutamide-resistant CRPC cells or in a VCaP CRPC model; higher levels of JMJD1A acetylation were associated with more rapid recurrence of prostate cancer after neoadjuvant hormone therapy, indicating a key role for JMJD1A acetylation in JMJD1A stability and CRPC progression. We have evidence that stability of acetylated JMJD1A requires BET family protein BRD4, which binds acetylated lysine and serves as promising targets for CRPC therapy. Interestingly, targeting JMJD1A acetylation using a p300 inhibitor or a BET inhibitor induces JMJD1A degradation and inhibits CRPC or NEPC cell growth in vitro. We will test the hypothesis that JMJD1A modifications by ubiquitination and acetylation regulate JMJD1A activity and may be targeted as potential CRPC and NEPC therapy.
Aim 1 characterizes biochemical mechanisms of JMJD1A acetylation in regulating JMJD1A recruitment to AR targets via BRD4.
Aim 2 will determine global regulation of AR target genes in CRPC cells upon manipulation of the STUB1-JMJD1A axis or JMJD1A acetylation using RNA-seq and ChIP-seq studies.
Aim 3 will evaluate growth of CRPC or NEPC xenografts following manipulation of the STUB1-JMJD1A axis or JMJD1A acetylation, or following treatment with a p300 inhibitor or a BET inhibitor. Finally, in Aim 4, we will evaluate effect of JMJD1A knockout in the progression and castration sensitivity of PTEN or Hi-Myc PCa models. We will also perform staining for acetylated JMJD1A and STUB1 in a large set of PCa tissue microarrays (TMAs) to evaluate how their expression correlates with JMJD1A levels, various types of prostate cancer and their clinical relevance. In summary, our proposed studies could identify novel mechanisms, targets and strategies useful as potential therapy for CRPC and NEPC.
We propose to characterize a new pathway that regulates JMJD1A function through ubiquitination and acetylation, modifications potentially relevant to AR/MYC activities and prostate cancer progression. Our studies should reveal new strategies to antagonize JMJD1A and concomitantly inhibit AR/MYC activities as potential prostate cancer therapy.