Epigenetic activation of CHST2 by promoter hypomethylation promotes progression of triple-negative breast cancer

Abstract

Epigenetic dysregulation is a hallmark of triple-negative breast cancer (TNBC), yet the oncogenic relevance of specific epigenetically activated genes remains poorly defined. In this study, we demonstrate that carbohydrate sulfotransferase 2 (CHST2) is aberrantly upregulated in TNBC across multiple transcriptomic analyses as a consequence of promoter hypomethylation. Elevated CHST2 expression is associated with aggressive clinicopathological characteristics and has been linked to unfavorable patient outcomes in independent cohorts. Functional analyses reveal that CHST2 primarily promotes TNBC cell migration and invasion, while genetic silencing of CHST2 markedly attenuates these malignant phenotypes. Importantly, mutational disruption of CHST2 catalytic activity abolishes its pro-migratory effects, indicating that sulfotransferase activity is essential for CHST2-driven invasiveness. Mechanistically, promoter hypomethylation is experimentally supported as a driver of CHST2 transcriptional activation, linking epigenetic deregulation to enhanced tumor aggressiveness. In addition, tumors with high CHST2 expression exhibit distinct immune-related transcriptional features within the tumor microenvironment. Collectively, these findings identify CHST2 as an epigenetically activated driver of invasive behavior in TNBC and highlight its potential value as a biomarker and therapeutic target for aggressive disease.