GSE176151
PLEKHG5 stabilized by HDAC2-related deacetylation is the master regulator of sorafenib resistance in HCC
Objective: Advanced HCC patients have few choices for life-prolonging therapy due to the high incidence of drug resistance. This study aimed to clarify the mechanism of sorafenib resistance and seek more effective treatments.Design:Two sorafenib-resistant (SR) cell lines were established to study the mechanism of drug resistance. RNA sequencing was used to characterize the global transcriptional consequences of sorafenib resistance, and immunoprecipitation-mass spectrometry (IP-MS) was performed to identify specific acetylation sites.Results: We found that Rho-GTPases were upregulated in SR cells and that PLEKHG5 was most abundantly expressed among all Rho GEFs (activators of Rho-GTPases). PLEKHG5 knockdown increased HCC cell sensitivity to sorafenib and inhibited the activation of Rac1 and downstream AKT/NF-?B signaling, while overexpression of PLEKHG5 reduced sorafenib sensitivity, which suggested that PLEKHG5 activation could be targeted to limit sorafenib resistance. IP-MS confirmed that three lysine sites in PH domain of PLEKHG5 could be acetylated, and their acetylation levels were correlated with PLEKHG5 stability. Further study demonstrated that HDAC2 interacted with PLEKHG5 to deacetylate lysine sites within the PH domain and maintain its stability. Finally, both knockout of HDAC2 and treatment with the selective HDAC2 inhibitor CAY10683 reduced PLEKHG5 protein levels and thereby enhanced the sensitivity of HCC to sorafenib in vivo and in vitro.Conclusion.:PLEKHG5 plays a key role in the occurrence of sorafenib resistance by activating Rac1/AKT/NF-?B signaling. HDAC2 regulates PLEKHG5 protein stability by regulating the acetylation level of its PH domain, and thus HDAC2 may be a potential therapeutic target for overcoming PLEKHG5-mediated sorafenib resistance in HCC. Overall design: mRNA profiles of MHCC97H control and sorafenib-resistant cells