LncRNA SEMA3B‐AS1 suppresses the tumor‐initiating characteristics of triple negative breast cancer via engaging in MLL4‐mediated H3K4 trimethylation

Abstract Long noncoding RNAs (lncRNAs) are crucial regulators of tumor‐initiating cells (TICs) and hold particular importance in triple negative breast cancer (TNBC). Yet, the precise mechanisms by which TIC‐associated lncRNAs influence TNBC remain unclear. Our research utilized The Cancer Genome Atlas Breast Cancer (BC) data set to identify prognostic lncRNAs. We then conducted extensive assays to explore their impact on the tumor‐initiating phenotype of TNBC cells and the underlying mechanisms. Notably, we found that low expression of lncRNA SEMA3B‐AS1 correlated with unfavorable survival in BC patients. SEMA3B‐AS1 was also downregulated in TNBC and linked to advanced tumor stage. Functional experiments confirmed its role as a TIC‐suppressing lncRNA, curtailing mammosphere formation, ALDH + TIC cell proportion, and impairing clonogenicity, migration, and invasion. Mechanistic insights unveiled SEMA3B‐AS1's nuclear localization and interaction with MLL4 (mixed‐lineage leukemia 4), triggering H3K4 methylation‐associated transcript activation and thus elevating the expression of SEMA3B, a recognized tumor suppressor gene. Our findings emphasize SEMA3B‐AS1's significance as a TNBC‐suppressing lncRNA that modulates TIC behavior. This study advances our comprehension of lncRNA's role in TNBC progression, advocating for their potential as therapeutic targets in this aggressive BC subtype.