Correlation between promoter methylation in the GSTP1 gene and hepatocellular carcinoma development: a meta-analysis

SIRT3, a class III histone deacetylase, has been implicated in various cancers as a novel therapeutic target. In hepatocellular carcinoma (HCC), we previously reported that SIRT3 induced cell apoptosis by regulating GSK-3β/Bax signaling pathway. Downregulation of SIRT3 in HCC cells facilitates tumor cell survival. In this study, we found that chemotherapeutic agents (doxorubicin, cisplatin and epirubicin) and sorafenib treatment downregulated SIRT3 mRNA and protein levels in three HCC cell lines. MTS assay found that SIRT3 overexpression sensitized liver cancer cells to chemotherapeutic agents and sorafenib in SMMC-7721, Huh-7 and PLC/PRF/5 cell lines. Moreover, SIRT3 overexpression promoted chemotherapeutic agents-induced or sorafenib-induced apoptosis as evidenced by flow cytometry, enhanced PARP cleavage and enhanced Caspase-9 cleavage in three HCC cells. In contrast, SIRT3 silencing increased drug resistance of HCC cells to chemotherapeutic agents. Mechanistic study found that SIRT3 downregulated the mRNA and protein levels of glutathione S-transferase pi 1 (GSTP1), which is a member of phase II detoxification enzymes families involved in metabolizing for chemotherapeutic agents. Moreover, SIRT3 decreased the amount of GSTP1 that was associated with JNK, which finally contributed the activation of JNK activity and activation of downstream target c-Jun and Bim. Importantly, GSTP1 overexpression or JNK inhibitor abolished SIRT3-induced apoptosis in HCC cells exposed to chemotherapeutic agents. Finally, there was a negative correlation between SIRT3 expression and GSTP1 expression in human HCC tissues. Together, our findings revealed SIRT3 could enhance the drug sensitivity of HCC cells to an array of chemotherapeutic agents. SIRT3 may serve as a potential target for improving the chemosensitivity of HCC patients.

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“…Cell apoptosis was determined by fluorescence-activated cell sorting (FACS) analysis as described [37]. …”

Section: Methodsmentioning

confidence: 99%

Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway

et al. 2016

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“…It has been shown that promoter hypermethylation is an epigenetic mechanism able to repress gene transcription by inhibiting the binding of transcription factors to their consensus sequences when methylated (Herman & Baylin, ). In the studies cited above, downregulation of GSTP1 gene expression was associated to an aberrant methylation in the promoter region (Chan et al., ; Li et al., ; Lin et al., ; Martignano et al., ; Mian et al., ; Shilpa et al., ; Zelic et al., ; Zhang et al., ). Moreover, promoter methylation of GSTP1 gene was detected in some body fluids of patients with prostate cancer and was proposed as a biomarker candidate for noninvasive detection of prostate cancer (Cairns et al., ; Goessl et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, it was reported that loss of GSTP1 expression enhances cell susceptibility to acquire additional alterations and undergo further genetic changes toward tumor progression (Schnekenburger, Karius, & Diederich, 2014). In this field, several research works found lower GSTP1 expression in prostate cancer (Lin et al, 2001;Martignano et al, 2016;Mian et al, 2016;Zelic et al, 2016;Zhang et al, 2015), endometrial cancer (Chan et al, 2005), hepatocellular cancer (Li, Li, Gao, & Shi, 2015), and ovarian cancer (Shilpa, Bhagat, Premalata, Pallavi, & Krishnamoorthy, 2014).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of glutathione S‐transferase pi 1 expression and gene promoter methylation in Moroccan patients with urothelial bladder cancer

Hadami

Dakka

Bensaid

et al. 2018

Molec Gen & Gen Med

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BackgroundGlutathione S‐transferase pi 1 (GSTP1) is a cytosolic detoxifying enzyme that protects cells against deleterious effects of oxidative stress. Deregulated expression of GSTP1 protein and aberrant promoter methylation of GSTP1 gene were reported in various human tumors and were shown to be involved in the molecular pathway for cancer development.Aims and methodsIn this study, we aimed to determine the expression status of GSTP1 in relation to its gene promoter methylation in Moroccan population of 30 bladder cancer (BC) patients and in two noncancerous bladder tissues used as controls. GSTP1 expression was assessed by immunohistochemistry and GSTP1 gene promoter methylation status was studied by methylation‐specific PCR (MS‐PCR).ResultsGlutathione S‐transferase pi 1 was expressed in the two normal tissues. In BC cases, GSTP1 expression was strong in 23.33% (7/30), moderate in 60% (18/30), and weak in 13.33% (4/30) of cases, while GSTP1 was not expressed in one cancer case (3.33%). Variability of GSTP1 expression does not correlate with high‐grade cancer or invasive‐stage (p > 0.05). No GSTP1 gene promoter methylation was detected in all control and cancer cases.ConclusionOur data suggest that GSTP1 expression is not associated with BC development, limiting its use as a biomarker for BC management in Morocco. Moreover, difference in GSTP1 expression among BC cases is not due to GSTP1 promoter methylation.

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“…GSTP1 methylation is frequently associated with tumor development or poor prognosis in a wide range of tumors such as neuroblastoma [6], hepatocellular carcinoma [7], endometrial [8], breast [9], and prostate cancers (PCa) [10]. It is involved in the early process of carcinogenesis in PCa [11, 12] and its methylation has been largely investigated: about 70–80% of PCa cases are methylated, while benign prostatic hyperplasias are normally hypomethylated [13, 14].…”

Section: Introductionmentioning

confidence: 99%

GSTP1Methylation and Protein Expression in Prostate Cancer: Diagnostic Implications

et al. 2016

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GSTP1 belongs to the GSTs family, a group of enzymes involved in detoxification of exogenous substances and it also plays an important role in cell cycle regulation. Its dysregulation correlates with a large variety of tumors, in particular with prostate cancer. We investigated GSTP1 methylation status with methylation specific PCR (MS-PCR) in prostate cancer (PCa) and in benign tissue of 56 prostatectomies. We also performed immunohistochemistry (IHC) so as to correlate gene methylation with gene silencing. GSTP1 appears methylated in PCa and not in healthy tissue; IHC confirmed that methylation leads to protein underexpression (p < 0.001). GSTP1 is highly expressed in basal cell layer and luminal cells in benign glands while in prostatic intraepithelial neoplasia (PIN) it stains only basal cell layer, whereas PCa glands are completely negative. We demonstrated that methylation leads to underexpression of GSTP1. The progressive loss of GSTP1 expression from healthy glands to PIN and to PCa glands underlines its involvement in early carcinogenesis.

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Correlation between promoter methylation in the GSTP1 gene and hepatocellular carcinoma development: a meta-analysis

Cited by 17 publications

References 37 publications

Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway

Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway

Evaluation of glutathione S‐transferase pi 1 expression and gene promoter methylation in Moroccan patients with urothelial bladder cancer

GSTP1Methylation and Protein Expression in Prostate Cancer: Diagnostic Implications

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