# Determine the Role of Histone Methyltransferase ASH1L in Metastatic Prostate Cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $537,699

## Abstract

Metastasis is the major cause of cancer mortality. Effective therapies are urgently needed for patients with
metastatic diseases. Increasing evidence suggests that interactions between cancer cells and tumor immune
microenvironment drive metastatic progression. Although prior studies established the vital roles of
immunosuppressive TME in metastatic progression, the epigenetic determinant in shaping the metastatic niche
remains understudied. Absent, small or homeotic 1-like (ASH1L) is a histone lysine methyltransferase that
induces methylations at H3K36 and . Although ASH1L was found to drive
leukemogenesis, little is known about its biological function in solid tumors and metastatic disease. Our
preliminary studies showed that ASH1L is genetically amplified and overexpressed in metastatic tumors and
contributes to metastasis and immunosuppression. The goal of this application is to determine the role and
mechanisms of action of ASH1L in the metastatic niche. The central hypothesis in this application is that histone
H3K4 and activates gene transcription
methyltransferase ASH1L contributes to the immunosuppressive metastatic niche and is a potential therapeutic
target in metastatic cancers. In the proposed studies, we will 1) determine ASH1L’s role in reshaping the
metastatic niche by combining a newly developed genetically engineered mouse model and cutting-edge single-
cell transcriptomic technologies; 2) elucidate the mechanism by which ASH1L induces immunosuppressive
metastatic niche by performing epigenetic profiling, proteomic approaches, and functional studies; 3) determine
the anti-metastatic effects of genetically depleting or pharmacologically inhibiting ASH1L in combination with
checkpoint immunotherapy in preclinical models, followed by profiling their impact on immune components in
the metastatic niche. We expect to identify ASH1L as a key epigenetic determinant in priming
immunosuppressive metastatic niche and develop effective targeted therapy and combinatorial immunotherapy
for metastatic cancers. These studies are expected to have significant positive impacts, including bridging the
knowledge gap on the role and mechanisms of action of an understudied epigenetic factor ASH1L in metastatic
cancers, advancing our understanding of the crosstalk between invading cancer cells and immune components
in the metastatic niche, and offering implications in regard to the biomarkers, therapeutic targets, and rational
combinations for metastatic malignancies.
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## Key facts

- **NIH application ID:** 10879288
- **Project number:** 1R01CA278889-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Di Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $537,699
- **Award type:** 1
- **Project period:** 2024-09-18 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879288

## Citation

> US National Institutes of Health, RePORTER application 10879288, Determine the Role of Histone Methyltransferase ASH1L in Metastatic Prostate Cancer (1R01CA278889-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879288. Licensed CC0.

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