Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy.

Abstract

Colorectal cancer (CRC) ranks among the primary causes of human mortality globally. Numerous studies have highlighted the significant role of PLOD3 in the progression of various cancers. However, the exact function and underlying mechanisms of PLOD3 in CRC remains incompletely understood. To investigate the expression of PLOD3, qRT‒PCR, immunohistochemistry and western blotting were utilized to analyze the expression of PLOD3 in CRC tissues and adjacent normal tissues. Functional assays were conducted to assess the roles of PLOD3 both in vitro and in vivo. To elucidate the potential mechanism of PLOD3 in CRC, a range of techniques, including coimmunoprecipitation, immunofluorescence, CHX pulse-chase, and ubiquitination assays were used. As the results indicated, hypomethylation of the PLOD3 promoter leads to its over- expression in CRC, and elevated PLOD3 levels are associated with a poor prognosis. Both in vitro and in vivo models demonstrated that PLOD3 enhances CRC cell proliferation, invasion, and migration. Furthermore, through mechanistic studies, TM9SF4 was identified as a protein that interacts with PLOD3 and contributes to CRC progression by promoting autophagy. Additionally, PLOD3 could be secreted by CRC cells and secreted PLOD3 could promote CRC cells migration and invasion. These results demonstrated that PLOD3 promotes CRC progression through the PLOD3/TM9SF4 axis and could be a potential biomarker and treatment target for CRC.