The VCPKMT-VCP-HDAC1 axis inhibits colorectal cancer by conferring sensitivity to ferroptosis

Ferroptosis, a regulated form of cell death driven by lipid peroxidation and iron dysregulation, plays a critical role in tumor suppression. The expression of certain genes determine ferroptosis sensitivity and may serve as biomarkers to identify patients who could benefit from ferroptosis-promoting therapies. The role of Methyltransferase-like (METTL) family proteins in colorectal cancer (CRC) tumorigenesis has gained increasing attention, yet the functional relevance of METTL21D (also known as VCPKMT) remains largely unexplored.

CCK8 assays, colony formation assays, and xenograft tumor experiments were used to investigate the role of VCPKMT in proliferation and ferroptosis sensitivity in CRC. RNA sequencing, IP-MS, and RT-qPCR were used to identify the relevant genes of VCPKMT. Co-IP and subcellular fractionation assays, western blotting and immunofluorescence (IF) staining were used to explore the underlying molecular mechanisms of actions of VCPKMT.

Herein, we identified that VCPKMT is downregulated in CRC tissues and lower VCPKMT expression correlates with ferroptosis resistance and poorer prognosis. Mechanistically, VCPKMT-induced VCP methylation facilitates its nuclear translocation, a process that enhances VCP's interaction with HDAC1. This interaction promotes the degradation of HDAC1 via the ubiquitin-proteasome pathway, leading to reduced expression of FTH1, a key inhibitor of ferroptosis. Combined targeting of HDAC1 and ferroptosis synergistically suppressed the growth of tumors with low VCPKMT expression.

Our findings reveal a novel role for VCPKMT as a regulator of ferroptosis sensitivity in CRC, highlighting the VCPKMT-VCP-HDAC1 axis as a potential therapeutic target for CRC treatment.