Circular RNA ACACA negatively regulated p53-modulated mevalonate pathway to promote colorectal tumorigenesis via regulating miR-193a/b-3p/HDAC3 axis.

Fengjiao He, Qiong Liu, Huan Liu, Qian Pei, Hong Zhu

Molecular carcinogenesis 2023 Jun

filter terms:

This study aimed to explore the biological functions and underlying mechanism of circRNA acetyl-CoA carboxylase alpha (circACACA) in colorectal cancer (CRC). The RNA and protein levels were detected by qRT-PCR and western blot assays. The malignant capacities of CRC cells were analyzed by cell counting kit-8 (CCK-8), colony formation, flow cytometry, and transwell assays. The target relationship between miR-193a/b-3p and circACACA/histone deacetylase 3 (HDAC3) was determined by luciferase reporter assay and RNA immunoprecipitation. The binding of HDAC3 to the p53 promoter was validated by chromatin immunoprecipitation (ChIP). CRC cell growth and lung metastasis were evaluated in nude mice in vivo. High expression of circACACA was found in CRC tissues and cells, which was closely associated with the advanced tumor, lymph node, metastasis (TNM) stage, metastasis, and low overall survival rate. circACACA downregulation effectively delayed CRC cell proliferation and metastasis, but triggered apoptosis via inactivating the mevalonic acid (MVA) pathway. However, circACACA overexpression resulted in the opposite effects. Mechanistically, circACACA enhanced HDAC3 expression through sponging miR-193a/b-3p, which activated the MVA pathway via inhibiting the acetylation and transcription of p53. Moreover, rescue experiments confirmed that miR-193a/b-3p inhibition reversed the inhibitory effect of circACACA deficiency on CRC growth and metastasis. Moreover, circACACA overexpression-mediated malignant phenotypes of CRC cells were abrogated by HDAC3 knockdown. circACACA promoted CRC progression via regulating the miR-193a/b-3p/HDAC3/p53 axis to activate the MVA pathway, providing evidence for circACACA as a promising therapeutic target for CRC. © 2023 Wiley Periodicals LLC.

Citation

Fengjiao He, Qiong Liu, Huan Liu, Qian Pei, Hong Zhu. Circular RNA ACACA negatively regulated p53-modulated mevalonate pathway to promote colorectal tumorigenesis via regulating miR-193a/b-3p/HDAC3 axis. Molecular carcinogenesis. 2023 Jun;62(6):754-770