Fatty acid dehydratase HACD3 poses protein kinase activity and promotes the malignant progression of colorectal cancer

HACD3 is a member belonging to the very long-chain fatty acid dehydratase family. However, little is known about HACD3's function besides its weak dehydratase activity. The current study aims to investigate the potential role of HACD3 in Colorectal Cancer (CRC). The study evaluates HACD3 expression in CRC patient samples. Moreover, the study investigates in vitro cell proliferation, colony formation, invasion, migration, and cell cycle progression on HACD3 knockdown and overexpressing CRC cells, along with in vivo tumorigenesis within NSG mice, Hacd3^-/-; Apc^Min/+ mice and Hacd3^ΔIEC; Apc^Min/+mice. The study identifies the molecular target(s) of HACD3 via phosphoproteomics, followed by biological assay verification. The study identifies that HACD3 is highly expressed in CRC tissues and promotes the malignant progression of cancer cells. Additionally, HACD3 interacts with CDK2, leading to CDK2 T160 phosphorylation via a domain between amino acids 298-324 of HACD3. Thus, fatty acid dehydratase HACD3 possesses protein kinase activity and stimulates tumorigenesis, partly by activating the CDK2 pathway. Therefore, inhibiting HACD3 could facilitate CRC treatment.