ZKSCAN5 transcriptional regulation of APOC1 modulates ferroptosis via PI3K/AKT/SREBP2/SLC1A5 axis.

Abstract

Background: Prostate cancer is a great substantial health challenge among the cancer type with a high incidence and serving as the main cause of cancer-related deaths in men. Apolipoprotein C1 encodes a member of the apolipoprotein C family. The APOC1 has been confirmed as an oncogene of prostate cancer. However, the mechanism of how the APOC1 protein influence remains to be elucidated.

Methods: The expression of APOC1 was detected in both prostate cancer tissues and prostate cancer cell lines. The APOC1 knockdown and overexpression cell models were created. The effect of APOC1 on prostate cancer cell proliferation,metastasis, EMT and ferroptosis were explored by colony formation, wound healing,transwell assays, CCK-8 and western blotting in vitro and subcutaneous tumor formation in nude mice. Furthermore, the mechanism of how APOC1 inhibits ferroptosis in prostate cancer through PI3K/AKT/SREBP2/SLC1A5 was detected. Meanwhile, the interaction of APOC1 and ZKSCAN5 (zinc finger with KRAB and SCAN domains 5) was determined using Chromatin Immunoprecipitation (ChIP).

Results: APOC1 expression was significantly upregulated in prostate cancer tissues and cell lines. Genetic silencing of APOC1 by shRNA demostrated potent tumor-suppressive effects, markedly inhibiting cell proliferation, metastasis and EMT, while concurrently enhancing ferroptosis rates. Then, APOC1 was shown to modulate cholesterol homeostasis via the PI3K/AKT/SREBP2/SLC1A5 signaling cascade, thereby influencing ferroptosis susceptibility in prostate cancer cells. Mechanistically, ZKSCAN5 was identified as a transcriptional repressor of APOC1 through direct promoter binding. Notably, the anti-ferroptosis function of APOC1 was mediated through SREBP2-dependent transcriptional regulation, with Cut&Tag (Cleavage Under Targets and Tagmentation) confirming SREBP-2's direct binding to the SLC1A5 promoter.

Conclusion: In prostate cancer, APOC1 regulates ferroptosis via PI3K/AKT/SREBP2/SLC1A5 axis, meanwhile ZKSCAN5 negatively regulates the expression of APOC1.