Triple-negative breast cancer (TNBC) represents a clinically aggressive breast cancer subtype with limited therapeutic options. Emerging evidence suggests that long intergenic noncoding RNA 00707 (Linc00707) plays a role in TNBC; however, the upstream regulators governing Linc00707 expression and the mechanisms by which it contributes to tumor progression remain largely undefined. The FOXP3-mediated transcriptional regulation of Linc00707 was analyzed using chromatin immunoprecipitation and luciferase reporter assays. The post-transcriptional regulation of Linc00707 was examined by RNA immunoprecipitation (RIP), methylated RIP, and RNA pull-down assays to assess WTAP-dependent m6A modification, IGF2BP2-mediated stabilization, and U2AF2 interaction. RNA sequencing and biochemical analyses were used to identify downstream regulatory pathways. The binding of oligo-anti-Linc00707 to Linc00707 and its ability to disrupt U2AF2 association were confirmed by RIP and RNA fluorescence in situ hybridization (RNA-FISH). Cellular assays and nude mouse xenograft models were employed to evaluate functional and therapeutic effects. FOXP3 was found to transcriptionally activate Linc00707 through direct promoter binding. The WTAP-mediated m6A modification enhanced the IGF2BP2-dependent stabilization of Linc00707. In the nucleus, Linc00707 interacted with the splicing factor U2AF2, with nucleotides 1–593 identified as a critical interaction region. Building on this observation, we further showed that the Linc00707–U2AF2 interaction functionally controls U2AF2 expression and stability via FOXP3. The Linc00707–U2AF2 complex was associated with altered alternative splicing of the autophagy-related gene ATG4B, contributing to enhanced TNBC cell proliferation, invasion, and autophagy suppression. Importantly, oligonucleotides complementary to the U2AF2-binding region of Linc00707 (oligo-anti-Linc00707) disrupted this interaction, attenuated Linc00707-driven oncogenic phenotypes, and restored autophagic activity. In vivo, oligo-anti-Linc00707 treatment significantly reduced tumor growth, supporting its therapeutic potential in TNBC. FOXP3 activates Linc00707 transcription in TNBC. WTAP-mediated m6A modification enhances Linc00707 stability via IGF2BP2. Linc00707 recruits U2AF2 to drive oncogenic ATG4B splicing, promoting tumor progression. Oligo-anti-Linc00707 specifically blocks Linc00707-U2AF2 complex formation, reversing its tumor-promoting and autophagy-suppressing functions. Thus, targeting Linc00707 represents a promising therapeutic strategy for TNBC.
Li et al. (Mon,) studied this question.