# The role and mechanism of RNA m6A modification in the pathogenesis and drug-resistance of prostate cancer

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $366,240

## Abstract

PROJECT TITLE:
The role and mechanism of RNA m6A modification in the pathogenesis and drug-resistance of prostate cancer
PROJECT SUMMARY (ABSTRACT):
Background: N6-methyladenosine (m6A) modification is the most prevalent and abundant internal modification in
eukaryotic messenger RNAs (mRNAs) and plays diverse and important roles in normal biological processes.
Emerging evidence suggest that m6A and m6A-assicated proteins also play critical roles in human diseases
including cancers. Prostate cancer (PCa) is the most commonly diagnosed cancer with the second leading
estimated deaths at the United States for more than a decade. Androgens and androgen receptor (AR) regulate
normal growth and function of the prostate gland. However, aberrant regulation of androgens and AR signaling
pathway are closely associated with PCa pathogenesis and progression. Thus, androgen deprivation therapies
(ADT) or targeting AR function have always been the mainstay of therapeutic strategy against advanced prostate
cancers. However, the current therapeutic strategies cannot cure most PCa patients due to drug resistance and
relapse, and eventually develop metastatic, castration-resistant prostate cancer (mCRPC), a lethal stage of the
disease. The acquired resistance to abiraterone and enzalutamide is considered as the main problem for the
treatment failure and relapse of PCa. Therefore, it is crucial to elucidate the molecular mechanisms underlying
PCa pathogenesis and drug resistance, which may contribute to the development of effective new therapeutic
approaches to overcome the limitations of current treatment for PCa. RNA m6A modification is deposited by m6A
methyltransferase complex composed of three core subunits METTL3, METTL14 and WTAP and may have
functions as an important regulator of gene expression that can affect mRNA transcription, splicing, export,
stability, and translation. Previously, we have reported that METTL3-catalyzed m6A modification of target mRNA
plays critical oncogenic roles in human cancers including PCa, but its definitive roles in AR signaling activation
and especially in drug-resistant AR signaling remain elusive. Our preliminary data imply that m6A modification
on enhancer RNAs (eRNAs), which are regulatory RNAs transcribed from non-coding enhancer elements, may
also have roles in drug resistance in PCa, which requires further systematic studies. The goal of this proposal is
to prove the central hypothesis that METTL3-mediated RNA m6A modification plays essential roles in AR
signaling, PCa pathogenesis and drug resistance. The m6A methylome of chromatin-associated regulator
RNAs (carRNAs) and nascent RNAs will be mapped, analyzed and correlated with the genome-wide binding of
AR and transcriptional machineries. Also, the role of YTHDC1, a nuclear m6A reader protein, will be systemically
examined to investigate its relationship with the transactivation of AR and genome-wide distribution, as it has
been known to regulate transcriptional activ...

## Key facts

- **NIH application ID:** 10818624
- **Project number:** 5R01CA279696-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Jihoon Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $366,240
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818624

## Citation

> US National Institutes of Health, RePORTER application 10818624, The role and mechanism of RNA m6A modification in the pathogenesis and drug-resistance of prostate cancer (5R01CA279696-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10818624. Licensed CC0.

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