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PLEKHG5 stabilized by HDAC2-related deacetylation is the master regulator of sorafenib resistance in HCC

ABSTRACT: PLEKHG5 stabilized by HDAC2-related deacetylation is the master regulator of sorafenib resistance in HCC

PROVIDER: PRJNA735183 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14730333_1.fastq.gz	Fastqsanger.gz
	SRR14730333_2.fastq.gz	Fastqsanger.gz
	SRR14730334_1.fastq.gz	Fastqsanger.gz
	SRR14730334_2.fastq.gz	Fastqsanger.gz
	SRR14730335_1.fastq.gz	Fastqsanger.gz

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PLEKHG5 stabilized by HDAC2-related deacetylation is the master regulator of sorafenib resistance in HCC

Project description: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-κB 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-κB 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.

2021-06-05 | GSE176151 | GEO

PLEKHG5 is stabilized by HDAC2-related deacetylation and confers sorafenib resistance in hepatocellular carcinoma.

Project description: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. Here, we found that PLEKHG5 (pleckstrin homology and RhoGEF domain containing G5), a RhoGEF, was highly upregulated in sorafenib-resistant cells. PLEKHG5 overexpression activated Rac1/AKT/NF-κB signaling and reduced sensitivity to sorafenib in HCC cells, while knockdown of PLEKHG5 increased sorafenib sensitivity. The increased PLEKHG5 was related to its acetylation level and protein stability. Histone deacetylase 2 (HDAC2) was found to directly interact with PLEKHG5 to deacetylate its lysine sites within the PH domain and consequently maintain its stability. Moreover, knockout of HDAC2 (HDAC2 KO) or selective HDAC2 inhibition reduced PLEKHG5 protein levels and thereby enhanced the sensitivity of HCC to sorafenib in vitro and in vivo, while overexpression of PLEKHG5 in HDAC2 KO cells reduced the sensitivity to sorafenib. Our work showed a novel mechanism: HDAC2-mediated PLEKHG5 posttranslational modification maintains sorafenib resistance. This is a proof-of-concept study on targeting HDAC2 and PLEKHG5 in sorafenib-treated HCC patients as a new pharmaceutical intervention for advanced HCC.

| S-EPMC10227013 | biostudies-literature

Effect of HDAC2 siRNA on HCC

Project description:Determine the effect and specificity of HDAC2 siRNA compared to SAHA inhibition of HDAC2 in hepatocellular carcinoma (HCC) Profile of treated cells compared to control Transcriptomic profiling

2014-10-02 | E-GEOD-52232 | biostudies-arrayexpress

Effect of HDAC2 siRNA on HCC

Project description:Determine the effect and specificity of HDAC2 siRNA compared to SAHA inhibition of HDAC2 in hepatocellular carcinoma (HCC)

2014-10-02 | GSE52232 | GEO

WDR5 promotes histone deacetylation via direct interaction with HDAC2 in human CCA cells.

Project description:WDR5 promotes histone deacetylation via direct interaction with HDAC2 in human CCA cells.

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Expression data from intestine of HDAC1 and HDAC2 conditionally mutated mice

Project description:Acetylation and deacetylation of histones and other proteins depend on the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), leading to either positive or negative gene expression changes. The use of HDAC inhibitors (HDACi) has uncovered a role for HDACs in the control of proliferation, apoptosis and inflammation. However, little is known of the roles of specific HDACs in intestinal epithelial cells (IEC). We investigated the consequences of ablating both Hdac1 and Hdac2 in murine IECs gene expression. HDAC1 and HDAC2 conditionally mutated mice were provided by Dr EN Olson (University of Texas Southwestern Medical Center, Dallas, TX) (Montgomery et al., 2007). Floxed HDAC1 and HDAC2 mice were crossed with villin-Cre transgenic mice to insure specific intestinal epithelial cell gene deletion (Madison et al., 2002). Total RNAs from the colon of three control and three HDAC1/2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).

2013-06-08 | E-GEOD-47745 | biostudies-arrayexpress

Quantitative Time-Course Profiling of Sorafenib-Treated Hepatocellular Carcinoma (HCC) Cells Through Phosphoproteome Analysis

Project description:Ferroptosis is a new form of regulated, non-apoptotic cell death characterized by excessive lipid peroxidation upon loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). Sorafenib, an FDA-approved multi-kinase inhibitor drug for treatment of hepatocellular carcinoma (HCC), has been shown to induce ferroptosis. Protein phosphorylation changes upon Sorafenib treatment have been previously reported in patient studies and in cell culture however the early phosphorylation changes during induction of ferroptosis are not completely understood. This work highlights these changes through a time course from 7 to 60 min of Sorafenib treatment in SKHep1 cells to provide insight on the induction of ferroptosis. 6,186 unique phosphosites were quantified from 2,381 phosphoproteins in this study and phosphorylation changes occurred in as early as 30 minutes of Sorafenib treatment. By 60 minutes, significant changes in key regulatory pathways were identified, including sites from ferroptosis-related proteins, indicating the involvement of phospho-regulated signaling during ferroptosis induction.

2019-07-26 | MSV000084140 | MassIVE

Expression data from sorafenib-resistant HCC cells, xenograft model and the corresponding counterparts.

Project description:To better identify the key gene involved in sorafenib-resistant HCC cells and uncover potential targets for HCC therapy, the microarray analysis was used to screen the differentially expressed genes in sorafenib-resistant HCC cells, xenograft model and the corresponding counterparts.

2021-10-11 | GSE121153 | GEO

Expression data from intestine of HDAC1 and HDAC2 conditionally mutated mice

2013-06-08 | GSE47745 | GEO

RNA-sequencing of HCC patients undergoing sorafenib treatment

Project description:RNA-sequencing of hepatocellular carcinomas at various stages of sorafenib treatment

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