The ubiquitination degradation of KLF15 mediated by WSB2 promotes lipogenesis and progression of hepatocellular carcinoma via inhibiting PDLIM2 expression.

Abstract

Background and aim: Krüppel-like factors15 (KLF15) is a cancer suppressor in many cancers. However, its precise function in the development of hepatocellular carcinoma (HCC) remains unclear. Lipogenesis is necessary for the development of HCC. This research aims to investigate the role of KLF15 in the regulation of hepatic lipid production and HCC progression.

Methods: The binding relationships among genes were confirmed by ChIP, dual luciferase assays, and Co-IP. Lipogenesis was examined by oil red O staining. Triglyceride and cholesterol levels were measured through commercial kits. The effect of treatment on HCC cell viability, proliferation, migration, and invasion were assessed using CCK-8, clone formation, or transwell assays. A subcutaneous tumorigenic model was utilized to explore the effects of PDLIM2 in HCC in vivo.

Results: KLF15 were downregulated in human HCC tissues. KLF15 overexpression reduced lipid droplet production, suppressed the expression of genes associated with lipogenesis, and promoted cell proliferation, migration, and invasion. KLF15 suppressed the NF-κB pathway through transcriptional activation of PDLIM2. PDLIM2 knockdown attenuated the effect of KLF15 overexpression on HCC. WSB2 degraded KLF15 through ubiquitination to promote HCC lipogenesis and development.

Conclusion: The ubiquitination degradation of KLF15 was mediated by WSB2, which led to transcriptional repression of PDLIM2 and further activation of the NF-κB pathway, ultimately promoting HCC lipogenesis and development.