Published online Sep 21, 2023. doi: 10.3748/wjg.v29.i35.5104
Peer-review started: June 25, 2023
First decision: August 8, 2023
Revised: August 10, 2023
Accepted: August 25, 2023
Article in press: August 25, 2023
Published online: September 21, 2023
Regulating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanism in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance characteristics of CRC cells may be related to their fat metabolism.
With the aging of the world population, the incidence of CRC is increasing. For the treatment of CRC, chemoresistance has always been an urgent problem to be solved.
This study aimed to explore the role of REG4 in CRC and its association with lipid droplet formation, and the molecular mechanisms involved.
We conducted a meta-analysis and bioinformatics and pathological analysis of REG4 expression in CRC. The effects of REG4 on the phenotypes and related proteins were also investigated in CRC cells.
Compared to normal mucosa, REG4 mRNA expression was high in CRC, but protein expression was opposite. REG4-related genes included epigenetic regulation, transcription repression, sugar metabolism and transfer. REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly, which was strengthened by high glucose treatment. REG4 inhibited the transcription of acetyl-coA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti–acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.
REG4 may be an indicator of drug resistance and metabolism of tumor cells. REG4 might be a useful marker for colorectal carcinogenesis, as well as a potential gene therapy target.
This study provides new insights into a better understanding of the pathogenesis of CRC. REG4 may be used as a novel therapeutic target. However, the regulatory mechanism needs to be further explored.