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Cancer Res., May 29 2025, | https://doi.org/10.1158/0008-5472.CAN-24-3476
CARM1-mediated MAP2K4 methylation potentiates the oncogenic functions of MAP2K4 and constitutes a targetable dependency in triple-negative breast cancer
Eui-Jun Kim1,2, Yidan Wang1,2, Yu-Lin Chen1,2, Min Ma3, Peng Liu2,6, Megan S. Bacabac1,2, Jingjing Zhou1,2, Christopher J Fry5, Jordan R. Hoffman5, Menggang Yu6,7, Lingjun Li3,4, Aussie Suzuki1,2, Shulin Li8, Wei Xu1,2,*
1McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA
2Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, WI 53705, USA
3School of Pharmacy, University of Wisconsin−Madison, Madison, Wisconsin 53705, USA
4Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, USA
5Cell Signaling Technology, Danvers, MA 01923
6Department of Biostatistics and Medical Informatics. School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
7Present address: Department of Biostatistics, University of Michigan School of Public Health, Ann Harbor, MI 48109, USA
8The University of Texas MD Anderson Cancer Center, Pediatrics – Research, Houston, TX 77030, USA
*Corresponding Author: Dr. Wei Xu
1McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA
2Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, WI 53705, USA
3School of Pharmacy, University of Wisconsin−Madison, Madison, Wisconsin 53705, USA
4Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, USA
5Cell Signaling Technology, Danvers, MA 01923
6Department of Biostatistics and Medical Informatics. School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
7Present address: Department of Biostatistics, University of Michigan School of Public Health, Ann Harbor, MI 48109, USA
8The University of Texas MD Anderson Cancer Center, Pediatrics – Research, Houston, TX 77030, USA
*Corresponding Author: Dr. Wei Xu
Abstract
The arginine methyltransferase CARM1 is amplified/overexpressed in a variety of cancers, including triple-negative breast cancer (TNBC), spurring the interest of developing CARM1 inhibitors (CARM1i). Here, we discovered that CARM1i treatment leads to elevated CARM1 levels as well as activation of AKT, which could result in long-term treatment resistance in breast cancer cells. CARM1 methylated MAP2K4 at arginine 58 in TNBC, and methylated-MAP2K4 localized to the nucleus and potentiated the proliferation- and metastasis-promoting function of MAP2K4 via activation of JNK signaling. Inhibition of MAP2K4 by CARM1i led to AKT activation, which was abrogated by treatment with a PI3K inhibitor (PI3Ki). Combining CARM1i and PI3Ki elicited synergistic anti-cancer effects in TNBC cell lines, organoids, and patient-derived xenografts. This study demonstrates that, through inhibiting MAP2K4 methylation, CARM1i abrogates the feedback loop of MAP2K4 and PI3K signaling, supporting treatment with CARM1i as a therapeutic approach to improve the sensitivity of TNBC to PI3Ki.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-06-02)
- 국외 연구진
- 의약학 > 종양의학
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