HOXA13 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating SLC7A11 and SLC3A2.

[BACKGROUND] HOXA13, a member of the homeobox gene family, has emerged as a potential oncogenic driver in prostate cancer (PCa). However, its regulatory role in ferroptosis and interactions with SLC7A11 and SLC3A2 remain unclear. This study investigates the functional significance of HOXA13 in PCa progression and its mechanistic link to SLC7A11/SLC3A2-mediated ferroptosis suppression.

[METHODS] HOXA13 expression in PCa tissues and cell lines was analyzed via RT-qPCR and Western blot. Functional assays (CCK-8, colony formation, wound healing, Transwell) and ferroptosis markers (ROS, MDA, iron levels) were evaluated in HOXA13-knockdown PCa cells. Transcriptional regulation of SLC7A11/SLC3A2 by HOXA13 was validated using ChIP-PCR, dual-luciferase reporter assays, and rescue experiments. In vivo tumor growth was assessed in nude mouse xenograft models. The positive signal of ki67, 4-HNE in tumor tissue was detected by immunohistochemical staining.

[RESULTS] HOXA13 was significantly upregulated in PCa tissues and cell lines compared to normal controls. HOXA13 knockdown elevated ROS, MDA, and intracellular iron levels, promoting ferroptosis, which was reversed by ferroptosis inhibitor (Ferrostatin-1). Knockdown HOXA13 inhibited PCa cell proliferation, migration, and invasion, partially rescued by SLC7A11/SLC3A2 overexpression. HOXA13 directly bound to promoters of SLC7A11 and SLC3A2, enhancing their transcription. SLC7A11/SLC3A2 reversed ferroptosis and restored tumor growth in vitro and in vivo. HOXA13 knockdown suppressed xenograft tumor growth in mice, while SLC7A11/SLC3A2 overexpression restored tumorigenicity.

[CONCLUSION] HOXA13 drives PCa progression by transcriptionally activating SLC7A11 and SLC3A2, which suppress ferroptosis and enhance proliferation and metastasis. The findings highlighted sh-HOXA13 promoting ferroptosis as a potential strategy for PCa treatment.