# Protein Arginine Methylation in Chemotherapy Resistance

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $160,001

## Abstract

PROJECT SUMMARY
Chemotherapy continues to be an important component of therapy for breast cancer, given to reduce the
risk of metastatic recurrence. Although response (sensitivity) or lack of response (resistance) to
chemotherapy is associated with prognosis, there is currently no validated commercial assay available
which specifically predicts response to chemotherapy. Personalized approaches to cancer therapy are
needed to select a drug or combination of drugs to which a tumor is most sensitive, and to avoid the toxicity
of drugs to which the tumor is or becomes resistant. Such biomarker will assist oncologists in the daily
clinical management of aging patients who are fragile to multiple chemotherapies and triple negative breast
cancer patients whose major treatment option is chemotherapy.
Coactivator associated arginine methyltransferase 1 (CARM1) is a protein arginine (R) methyltransferase
which can methylate histone H3 and a variety of non-histone substrates. We recently identified a mediator
of RNA polymerase II transcription subunit 12 (MED12) as a novel substrate for CARM1. The proposed
project will determine whether methylation of MED12 is a predictor for chemo-sensitivity in breast cancer.
We have mapped the methylation sites of MED12 to R1862 and R1912. Coincidently, mutations on R1862
had been reported in lung and cervical cancers, and mutations on R1912 had been found in a melanoma
patient who developed resistance to BRAF inhibitor. We found that overexpression of MED12 wild-type, but
not MED12R1862K,R1912K mutant, increased sensitivity of HEK293 cells to 5-FU and anthracyclines.
Interestingly, the MED12 methylation dependent mechanism is distinct from activation of TGF-βR signaling
as reported for complete knockout of MED12 in lung and colon cancers. Further, we have identified targets
regulated by methylated MED12 that may determine chemo-sensitivity. We hypothesize that methylation of
MED12 by CARM1 represents an important mechanism conferring chemosensitivity. The proposed
research will directly address (1) whether MED12 methylation predicts sensitivity of breast cancer cells to
commonly used chemotherapies in cell culture and xenograft tumor models; (2) define the mechanism of
methylated-MED12 controlled chemosensitivity; and (3) test the clinical relevance of the MED12 methylation
in chemo- resistance using large cohorts of clinical specimens. The goal is to delineate the methylation
dependent mechanism for chemotherapy resistance and uncover new targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 9838157
- **Project number:** 5R01CA213293-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Wei Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $160,001
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838157

## Citation

> US National Institutes of Health, RePORTER application 9838157, Protein Arginine Methylation in Chemotherapy Resistance (5R01CA213293-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838157. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*