# Epigenetic Silencing of Inhibitor of Differentiation 4 (ID4) Promotes Stem Cell and Castration Resistant Phenotype in Prostate Cancer > **NIH NIH U54** · CLARK ATLANTA UNIVERSITY · 2024 · $196,351 ## Abstract PROJECT SUMMARY/ABSTRACT PROJECT 2 Androgen receptor (AR), is essential for normal prostate development where it acts mainly as a tumor suppressor. In prostate cancer (PCa), AR transitions to a potent oncogene by supporting the survival of cancer cells. ID4, a helix loop helix (HLH) transcriptional regulator, is tumor suppressor that is epigenetically silenced in PCa and PCa cell lines DU145, C-81 and PC3. We have shown that in Id4-/- mice and in ID4 depleted PCa cell line LNCaP ((LNCaP(-)ID4)), ID4: a) attenuates prostate development, b) promotes PIN by attenuating tumor suppressors (PTEN, p53, NKX3.1) and promoting tumor promoters (Myc, Id1, pAKt and Sox9) without altering AR expression, c) AR is re-directed from occupying promoters of tumor suppressors (NKX3.1) to tumor promoters (FKBP51 and MYC), d) promotes tumorigenicity in castrated nude mice (CRPC phenotype) and e) promotes the expression AMACR (PCa Marker) and, e) promotes stem cell phenotype/ markers (sca1 in Id4-/- mice, ALDH1A1 and ALDH1A3, CD133/ 44, Nanog and SOX2 in LNCaP(-)ID4 cells). Because tumor regenerating prostate cancer stem (PCSC) cells play a role in therapy resistance and progression to advanced PCa, targeting AR in PCSC in an ID4 depleted background may be a promising and effective strategy to combat CRPC. However, the molecular mechanism, by which ID4 cross-talks with AR and regulates the stem cell population is not known. Our hypothesis for this proposal, is “inactivation of ID4 promotes stem cell like properties and CRPC via redirecting androgen receptor activity that fuels aggressive growth”. The hypothesis will be addressed by: Aim1: Investigate the role of ID4 in regulating PCa stemness and Aim2: Investigate the molecular mechanism by which loss of ID4 promotes CRPC. We will address the underlying mechanism by which ID4 is epigenetically silenced in PCa through a crosstalk between PRMT1 and EZH2 and how loss of ID4 promotes stem cell phenotype. The underlying mechanism and whether these stem cells are castration resistant, are regenerative, clonogenic and forms tumor that maintains castration resistance will be the focus of Aim1. We have demonstrated that inactivation of ID4 could lead to CRPC through multiple pathways including up-regulation pAKT and AR co-chaperone FKBP52. The majority of CRPC maintain AR-dependent signaling as evident by re-elevation of PSA. Hence the role of ID4 in regulating AR activity appears significant in context of CRPC (The AR cistrome, SA2). Loss of ID4 leads to the convergence of multiple oncogenic pathways which can be exploited for developing a combinatorial therapeutic strategy by:1) up-regulating ID4 by blocking epigenetic pathways (e.g. PRMT1), 2) targeting the pro-survival/ anti-apoptotic AKT pathway by blocking pAKT and 3) targeting the CRPC pathway by blocking androgen receptor co-chaperone FKBP52. The targeted pathways individually are well documented in PCa and the small molecules targeting these pathways have an establi... ## Key facts - **NIH application ID:** 10800519 - **Project number:** 2U54MD007590-37 - **Recipient organization:** CLARK ATLANTA UNIVERSITY - **Principal Investigator:** JAIDEEP CHAUDHARY - **Activity code:** U54 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $196,351 - **Award type:** 2 - **Project period:** 1997-06-01 → 2029-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10800519 ## Citation > US National Institutes of Health, RePORTER application 10800519, Epigenetic Silencing of Inhibitor of Differentiation 4 (ID4) Promotes Stem Cell and Castration Resistant Phenotype in Prostate Cancer (2U54MD007590-37). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10800519. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*