# Deciphering the Impact of ZNF397-deficiency in Promoting TET2-driven Epigenetic Rewiring, Lineage Plasticity, and Therapy Resistance in Prostate Cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $8,266

## Abstract

PROJECT SUMMARY
 Phenotypic plasticity and epigenetic reprogramming stand as two noteworthy cancer hallmarks. Lineage
plasticity, in particular, has been recognized as a key mechanism that enables cancer cells to evade targeted
therapies. Prostate cancer (PCa), especially its most aggressive form, metastatic castration-resistant prostate
cancer (mCRPC), exemplifies lineage plasticity-based resistance to Androgen Receptor (AR) targeted therapies.
This resistance significantly constrains patient clinical outcomes, rendering mCRPC incurable, underscoring the
critical demand for elucidating the mechanisms of resistance and identifying actionable therapeutic targets to
overcome resistance. We identified ZNF397 as a pivotal coactivator for AR expression, essential for the
transcriptional program governing AR-driven luminal lineage in various cancers. ZNF397 deficiency, a prevalent
event observed in 25-40% of PCa patients, enables the transition of cancer cells from an AR-driven luminal
lineage to a TET2-driven lineage plastic state, consequently leading to AR therapy resistance. Preliminary results
also suggest that both genetic and pharmaceutical inactivation of TET2 eradicates AR targeted therapy
resistance, highlighting TET2 as a potential therapeutic target to combat AR targeted therapy resistance in
advanced PCa, including mCRPC. Therefore, the Overall Objective of this study is to comprehensively decipher
the molecular mechanism of ZNF397-deficiency in promoting lineage plasticity and AR-targeted therapy
resistance, with a goal to develop innovative therapeutic approaches to overcome resistance and benefit patients
suffering from this devastating disease. We proposed three aims to test the hypothesis that the frequently
observed ZNF397-deficiency is a molecular driver that promotes the transition of cancer cells from an AR-driven
luminal lineage state to a TET2-driven lineage plastic state, which subsequently becomes non-responsive to AR-
targeted therapy. In Aim 1, we will comprehensively assess the effect of ZNF397-deficiency in PCa
tumorigenesis, therapy responsiveness and lineage plasticity, using our uniquely generated GEMM with
ZNF397-KO, as well as single cell RNA-seq and spatial transcriptomics. In Aim 2, we will elucidate the molecular
mechanism of TET2-driven epigenetic rewiring and lineage plasticity in ZNF397-deficient PCa. In Aim 3, we will
assess the predictive potency of ZNF397 expression as a biomarker for AR targeted therapy response and
examine the efficacy of two novel strategies to overcome resistance in ZNF397-deficient tumors: TET2 inhibitors
and ZNF397-DUBTACs. The proposed aims will capitalize on our laboratory's expertise and that of our
collaborators to comprehensively define the molecular function of ZNF397. Completion of this project will not
only refine our understanding of the mechanisms propelling AR-targeted therapy resistance but also lead to a
new predictive biomarker and two innovative therapeutic strategies to ...

## Key facts

- **NIH application ID:** 10856068
- **Project number:** 1R01CA288820-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ping Mu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $8,266
- **Award type:** 1
- **Project period:** 2024-05-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10856068

## Citation

> US National Institutes of Health, RePORTER application 10856068, Deciphering the Impact of ZNF397-deficiency in Promoting TET2-driven Epigenetic Rewiring, Lineage Plasticity, and Therapy Resistance in Prostate Cancer (1R01CA288820-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10856068. Licensed CC0.

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