# Targeting interplay between KLF4 and PRMT5 in carcinogenesis

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $253,214

## Abstract

Targeting the interplay between KLF4 and PRMT5 in carcinogenesis
The goal of this project is to determine the impact of interplay between KLF4 and PRMT5 in breast
carcinogenesis and anti-breast cancer therapy. Krüppel-like factor 4 (KLF4) is a critical regulator of cell
fate for cell division, apoptosis, and DNA damage, and plays an ambivalent role in tumorigenesis.
Over 70% of human primary mammary cancers exhibit cellular accumulation of KLF4, and the impact
of KLF4 on breast cancer formation has been recently indicated by the TCGA (The Cancer Genome
Atlas). The most recent studies by us and others have demonstrated an oncogenic role for KLF4 in
breast carcinogenesis. Nevertheless, how KLF4 is regulated and how its deregulation contributes to
breast carcinogenesis remains unknown. Results from our recent purification of the KLF4 protein
complex revealed that two critical enzymes, VHL and PRMT5, tightly interact with and regulate KLF4.
While the ubiquitin E3 ligase VHL/VBC catalyzes KLF4 for ubiquitylation followed by degradation, we
observed that methylation of KLF4 protein by PRMT5 (an arginine-based methyltransferase) results in
the stabilization of KLF4 and promotion of KLF4-mediated transcription. Unexpected elevation of KLF4
levels due to enhanced KLF4 methylation counteracts KLF4 ubiquitylation, which in turn triggers tumor
initiation and promotes tumor invasion. We further observed that deregulation of KLF4 methylation by
aberrant PRMT5 expression impairs DNA damage checkpoint function, which could induce malignant
transformation due to loss of genomic integrity. Thus, we ask if PRMT5 is a critical factor that
determines the oncogenic role for KLF4 in breast carcinogenesis, and if the PRMT5-KLF4 cascade
could be a novel target for breast cancer therapy. This proposal aims to determine the
pathophysiological role of KLF4 methylation by PRMT5 in mammary tumorigenesis, and to further
identify the clinical relevance of the KLF4-PRMT5 axis in breast cancer therapy. In this project, we
plan to test the hypothesis that deregulation of KLF4 by PRMT5 promotes tumorigenesis and tumor
invasion by pursuing the following specific aims: (1) to determine how methylation of KLF4 by PRMT5
regulates KLF4 protein stability and function; (2) to determine how the dysregulation of KLF4 by
PRMT5 affects the self-renewal of breast cancer stem cells and promotes tumorigenesis; and (3) to
determine the impact of deregulation of KLF4 by PRMT5 in breast tumor progression/invasion and
validate the therapeutic intervention of our newly developed KLF4 methylation inhibitor in breast
cancer treatment using murine models.

## Key facts

- **NIH application ID:** 9977693
- **Project number:** 5R01CA202963-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Yong Wan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $253,214
- **Award type:** 5
- **Project period:** 2016-07-08 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977693

## Citation

> US National Institutes of Health, RePORTER application 9977693, Targeting interplay between KLF4 and PRMT5 in carcinogenesis (5R01CA202963-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977693. Licensed CC0.

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