PLEKHG5, Stabilized by HDAC2-Related Deacetylation, Confers Sorafenib Resistance Through Regulating Rac1/AKT/NF-κB Signaling in HCC

Background: Sorafenib is the first FDA approved first-line targeted drug for advanced HCC. However, resistance to sorafenib is frequently observed in clinical practice, and the molecular mechanism remains largely unknown. This study aimed to clarify the mechanism of sorafenib resistance and seek more effective treatments for HCC.Methods: Two sorafenib-resistant (SR) cell lines were established by continuous exposure to sorafenib. Global transcriptional consequences of sorafenib-resistant HCC was characterized, and immunoprecipitation-mass spectrometry (IP-MS) was performed to identify specific acetylation sites.Findings: PLEKHG5 was abundantly up-regulated in HCC patients and sorafenib-resistant cells, which was correlated with poor outcomes in HCC patients. PLEKHG5 overexpression activated the Rac1/AKT/NF-κB signaling and reduced sensitivity to sorafenib in HCC cells, while knockdown of PLEKHG5 increased sorafenib sensitivity. Histone deacetylase 2 (HDAC2) was directly interacted with PLEKHG5 to deacetylate its lysine sites within the PH domain and consequently maintain its stability. Moreover, HDAC2 inhibition (HDAC2 knockout or inhibitor) induced PLEKHG5 acetylation-related degradation and thereby enhanced the sensitivity of HCC to sorafenib in vitro and in vivo.Interpretation: Our work showed a novel mechanism for maintaining sorafenib resistance by HDAC2-mediated PLEKHG5 posttranslational modifications, and is a proof-of-concept study for targeting HDAC2 and PLEKHG5 in sorafenib-treated HCC patients as a new pharmaceutical intervention for advanced HCC.Funding Information: This work was supported by grants from the National Natural Science Foundation of China (no. 81602045; no. 81802454; no. U20A20392), the Basic and frontier research project of Yuzhong District, Chongqing (no. 20180118), and the Natural Science Foundation Project of Chongqing (no. cstc2016jcyjA0206). Declaration of Interests The authors declare that they have no competing interests.Ethics Approval Statement: The Institute Research Medical Ethics Committee of First Affiliated Hospital of Chongqing Medical University (Chongqing, China) granted approval for this study. At the time of tissue collection, informed consent was obtained from all patients.