FBW7-Mediated Degradation of CHD3 Suppresses Hepatocellular Carcinoma Metastasis and Stemness to Enhance Oxaliplatin Sensitivity

Abstract

Background: Ubiquitination plays a key role in various cancers, and F-box and WD repeat domain containing 7 (FBW7) is a tumor suppressor that targets several cancer-causing proteins for ubiquitination. This paper set out to pinpoint the role of FBW7 in hepatocellular carcinoma (HCC). Methods: The target proteins of FBW7 and the expression of hromodomain helicase DNA binding protein 3 (CHD3) were analyzed in liver HCC (LIHC) samples using the BioSignal Data website. The effects of CHD3 and FBW7 on HCC cell viability, migration, invasion and stemness were investigated through cell counting kit (CCK)-8, wound healing, transwell and sphere formation assays. Detection on CHD3 and FBW7 expressions as well as their relationship was performed employing quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunoprecipitation, ubiquitination and western blot analyses. Results: The prediction of Ubibrowser revealed CHD3 as a target protein of FBW7. The data of starBase exhibited a higher expression level of CHD3 in LIHC samples relative to normal samples. CHD3 was upregulated in HCC cells. CHD3 knockdown inhibited HCC cell proliferation, migration, invasion, stemness and oxaliplatin sensitivity. FBW7 targeted CHD3 for ubiquitination. FBW7 overexpression restrained HCC cell migration, invasion and stemness, and attenuated the effects of overexpressed CHD3 on promoting migration, invasion, stemness and oxaliplatin resistance in HCC cells. Conclusion: FBW7 overexpression suppresses HCC cell metastasis, stemness and oxaliplatin resistance via targeting CHD3 for ubiquitylation and degradation.