Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy with few effective treatment options. Lenvatinib is the first-line therapy for HCC but has only limited clinical benefit. Here, we explored the role and mechanism of the WD repeat domain 4 (WDR4) in lenvatinib resistance to improve clinical benefit. We found that lenvatinib-resistant HCC tissues/cells exhibited increased the N7-methylguanosine (m7G) modification and WDR4 expression. By a gain/loss of function experiment, we showed that WDR4 promoted HCC lenvatinib resistance and tumor progress both in vitro and in vivo. By proteomics analysis and RNA immunoprecipitation PCR, we found that tripartite motif protein 28 (trim28) was an important WDR4 target gene. WDR4 promoted TRIM28 expression, further affected target genes expression, and thus increased cell-acquired stemness and lenvatinib resistance. Clinical tissue data showed that TRIM28 expression was correlated with WDR4 levels, and the expression of both was positively correlated with poor prognosis. Our study provides new insight into the role of WDR4, suggesting a potential therapeutic target to enhance the lenvatinib sensitivity of HCC.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
