Role of NF90 in Prostate Cancer

Project: Research project

Description

Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer and the third leading
cause of cancer deaths in American men. While early-stage PCa can be effectively treated with
surgery and radiation therapy, metastatic prostate cancer remains a challenge and androgen
deprivation therapy (ADT) is the mainstay treatment. Although a majority of advanced PCa
initially responds well to ADT, they ultimately develop resistance and become castration-resistant, called CRPC. CRPC tumors no longer need androgen to grow but often remain dependent on an aberrantly active androgen receptor (AR). Understanding the mechanisms to this androgen
-independent AR activation may shed significant light on effective strategies to eradicate CRPC.
EZH2 is an enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2) that catalyzes histone H3
lysine 27 trimethylation to suppress gene expression, a role that can be effectively targeted by enzymatic EZH2 inhibitors . Recent evidence suggests that EZH2 may have PRC2-independent
roles in activating gene expression. However, critical gaps remain as to what are the target genes, how EZH2 activates them, and how they work in concert with the epigenetic roles of EZH2 to promote CRPC. Our preliminary results showed that AR is a direct target of EZH2-mediated transcriptional activation. This activation is likely mediated by EZH2-interacting co-activator NF90, a dsRNA-binding protein.
Our preliminary data further showed that NF90 is up -regulated in CRPC and exhibits oncogenic functions. The roles of NF90, however, have never been studied in PCa. We hypothesize that NF90 cooperates with EZH2 in transcriptional activation, contributes to androgen-independent AR activation,
and promotes CRPC progression. To test these hypotheses, three Specific Aims are proposed.
Aim 1 will determine how NF90 interacts with EZH2 protein to mediate EZH2-induced AR expression. Aim 2 will determine how NF90 regulates EZH2 chromatin recruitment and target gene activation
using ChIP -seq and RNA-seq assays and examine the expression of NF90 in primary tissues to
determine its correlation with EZH2 expression and clinical outcome. Lastly, Aim 3 will characterize the roles of NF90 in prostate cancer in vitro and in vivo and, most importantly, test the efficacy of a new combinatorial therapeutic approach that simultaneously blocks the dual roles of EZH2 using enzymatic EZH2 inhibitor GSK126 and AR antagonist enzalutamide in PCa patient-derived xenograft (PDX) models.
StatusActive
Effective start/end date8/15/187/31/23

Funding

  • National Cancer Institute (5R01CA227918-02)

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Prostatic Neoplasms
Androgen Receptors
Androgens
Polycomb Repressive Complex 2
Transcriptional Activation
Androgen Receptor Antagonists
Gene Expression
Neoplasms
Castration
Therapeutics
Heterografts
Epigenomics
Histones
Lysine
Chromatin
Cause of Death
Carrier Proteins
Radiotherapy
RNA
Genes