# Epigenetic Mechanisms of Biliary Epithelial Neoplasia

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $347,700

## Abstract

Project Description
 Cholangiocarcinoma (CCA) is a highly malignant epithelial cancer of the
biliary tree. The incidence and mortality of CCA is rising worldwide and currently
there is no effective chemoprevention or treatment. The molecular pathogenesis
underlying biliary epithelial neoplasia involves genetic and epigenetic changes
leading to alterations of oncogenic and tumor suppressive pathways. While
recent high throughput next-generation sequencing analyses have aided the
identification of genetic abnormalities in CCA, the potential impact of epigenetic
alterations on biliary epithelial neoplasia remains largely unknown.
 The current proposal is based on our exciting preliminary studies that
EZH2 is a pivotal histone methyltransferase that epigenetically silences the
expression of tumor suppressor miR-34a through H3K27 trimethylation in biliary
cancer cells, and that miR-34a suppresses CCA cell growth by targeting Notch1,
Notch2 and Jagged1. Our experimental findings support the hypothesis that the
EZH2 histone methyltransferase promotes biliary carcinogenesis through
epigenetic silencing of miR-34a and subsequent activation of Notch signaling,
and that EZH2 inhibition or miR-34a replacement therapy in conjunction with
standard chemotherapeutic regimen may represent an effective strategy for the
treatment of human CCA. These hypotheses will be evaluated in two
complementary Specific Aims. In Specific Aim 1, we will evaluate the effect and
mechanism of the EZH2 histone methyltransferase in biliary carcinogenesis.
Studies will be carried out to determine EZH2-regulated gene expression profile
and its mechanism of action. The impact of EZH2 knockdown or overexpression
on CCA development will be assessed in two complementary mouse models of
cholangiocarcinogenesis (induced via transduction of the biliary tree and via
hydrodynamic tail vein injection). The relevance of EZH2 and related signaling
molecules will be validated in human CCA tissues and pre-cancerous bile duct
lesions. In Specific Aim 2, we will evaluate the therapeutic efficacy of EZH2
inhibition or miR-34a replacement in conjunction with standard chemotherapy in
pre-clinical models of CCA. The proposed studies will define the biological
functions and molecular mechanisms of EZH2 and related signaling molecules in
biliary carcinogenesis and lead to the development of new epigenetics-based
target therapy.

## Key facts

- **NIH application ID:** 9966916
- **Project number:** 5R01CA219541-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Tong Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,700
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966916

## Citation

> US National Institutes of Health, RePORTER application 9966916, Epigenetic Mechanisms of Biliary Epithelial Neoplasia (5R01CA219541-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966916. Licensed CC0.

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