CARM1-Mediated MAP2K4 Methylation Potentiates the Oncogenic Functions of MAP2K4 and Constitutes a Targetable Dependency in Triple-Negative Breast Cancer.

ABSTRACT: The arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1) is amplified/overexpressed in a variety of cancers, including triple-negative breast cancer (TNBC), spurring the interest of developing CARM1 inhibitors (CARM1i). In this study, 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 functions 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. Combining CARM1i and PI3K inhibitor eli

SUBMITTER: Kim EJ 

PROVIDER: S-EPMC12216741 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature