DNA methylation and histone acetylation regulate the expression of MGMT and chemosensitivity to temozolomide in malignant melanoma cell lines

Chen, Yaping; Hou, Xiaoyang; Yang, Chunsheng; Jiang, Xiaoxiao; Yang, Ming; Xu, Xianglai; Feng, Shouxin; Liu, Yanping; Guan, Jun

doi:10.1007/s13277-016-4994-1

Cited by 21 publications

(4 citation statements)

References 26 publications

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“…Gene silencing and loss of expression of MGMT, tumor suppressor gene, was reported in various types of cancers including breast cancer, colorectal cancer, nonsmall-cell lung cancer, melanoma, gliomas, and gastric cancer that is not related to gene mutations, deletions, rearrangements, or RNA instability. 37,38 Hypermethylation in specific region of promoter was suggested as one of the possible mechanisms for MGMT gene silencing in various cancers. 10,11 In the case of breast cancer, the earlier studies have estimated the frequency of MGMT promoter methylation between 22% and 32%.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of BRCA‐1 and MGMT genes, and histones H4 and H3 are associated with breast tumors

Paydar

Asadikaram

Nejad

et al. 2019

J of Cellular Biochemistry

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Aberrant patterns in promoter methylation of tumor-suppressor genes and posttranslational modifications of histone proteins are considered as major features of malignancy. In this study, we aimed to investigate promoter methylation of three tumor-suppressor genes (BRCA-1, MGMT, and P16) and three histone marks (H3K9ac, H3K18ac, and H4K20me3) in patients with breast tumors. This case-control study included 27 patients with malignant breast tumors (MBT) and 31 patients with benign breast tumors (BBT). The methylation-specific PCR was used for determining promoter methylation of BRCA-1, MGMT, and P16 genes. Western blot analysis was performed to detect histone lysine acetylation (H3K9ac and H3K18ac) and lysine methylation (H4K20me3). BRCA-1 promoter methylation was detected in 44.4% of the MBT whereas this alteration was found in 9.7% of BBT (P = 0.005). The Kaplan-Meier analysis indicated that hypermethylation in BRCA-1 promoter was significantly associated with poor overall survival of patients with breast cancer (P = 0.039). MGMT promoter methylation was identified in 18.5% of MBT and 0.0% of the BBT (P = 0.01). The frequency of P16 promoter methylation was 25.8% in BBT and 11.1% in MBT (P = 0.12). As compared with BBT, MBT samples displayed the aberrant patterns of histones marks with hypomethylation of H4K20 and hypoacetylation of H3K18 (P = 0.03 and P = 0.04, respectively). There was a negative significant correlation between H3K9ac levels and tumor size in MBT group (r = −0.672; P = 0.008). The present findings suggest that promoter hypermethylation of MGMT and BRCA-1 genes along with alterations in H3K18ac and H4K20me3 levels may have prognostic values in patients with breast cancer. Moreover, the detection of these epigenetic modifications in breast tumors could be helpful in finding new methods for breast cancer therapy. K E Y W O R D S breast cancer, breast tumor, epigenetic, histone modification, promoter methylation, tumor suppressor J Cell Biochem. 2019;120:13726-13736. wileyonlinelibrary.com/journal/jcb 13726 |

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Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of BRCA‐1 and MGMT genes, and histones H4 and H3 are associated with breast tumors

Paydar

Asadikaram

Nejad

et al. 2019

J of Cellular Biochemistry

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“…Although the etiology of pituitary adenoma is not fully understood, numerous experimental and clinical observations indicate that DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) is implicated in the pathogenesis of various tumor types, including pituitary adenoma ( 2 , 3 ). MGMT is a ubiquitous highly expressed enzyme that removes alkylating lesions at the O 6 position of guanine to repair DNA damage ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA induces apoptosis via inhibition of Wnt/β-catenin/MGMT signaling in AtT-20 cells

Huang

Chen

et al. 2017

Molecular Medicine Reports

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A strategy to suppress the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) by inhibition of Wnt/β-catenin signaling may be useful as a novel treatment for pituitary adenoma. Previous studies have reported that Tanshinone IIA (TSA), a major quinone compound isolated from Salvia miltiorrhiza, had antitumor effects. However, whether TSA has antitumor effects against pituitary adenoma and whether the mechanisms are associated with the Wnt/β-catenin/MGMT pathway remains to be clarified. In the present study, TSA treatment caused apoptosis in AtT-20 cells in a concentration-dependent manner, as demonstrated by cell viability reduction, phophatidylserine externalization detected by Annexin V staining and mitochondrial membrane potential disruption detected by JC-1 staining, which were associated with activation of caspase-3 and DNA fragmentation detected by TUNEL in AtT-20 cells. T-cell factor (TCF)-lymphoid-enhancing factor (LEF) reporter activity was determined by dual luciferase reporter assay and the interaction between β-catenin and TCF-4 were detected using a co-immunoprecipitation kit. The results indicated TSA treatment increased β-catenin phosphorylation, inhibited β-catenin nuclear translocation, reduced β-catenin/TCF-4 complex formation and TCF-LEF luciferase reporter activity, and subsequently reduced the expression of cyclin D1 and MGMT. Notably, overexpression of MGMT in β-catenin knock down AtT-20 cells abrogated the TSA-mediated effects in AtT-20 cells. In conclusion, TSA induced apoptosis via inhibition of Wnt/β-catenin-dependent MGMT expression, which may provide novel insights into the understanding of the mechanism of the antitumor effects of Salvia miltiorrhiza.

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“…The combination of HDAC inhibitors and DNMT inhibitors increases chromatin accessibility to cisplatin and doxorubicin, thus potentiating the anticancer effect of these cytotoxic drugs [ 134 ]. In addition, the combination of the DNMT inhibitor 5-aza-2′-deoxycytidine and the HDAC inhibitor trichostatin A sensitizes melanoma cells to temozolomide [ 135 ]. A phase I clinical trial studying the combination of decitabine and panobinostat with temozolomide reported that this triple therapy is safe in resistant metastatic melanoma patients and that 75% of the patients enrolled in the trial had either stable disease or complete response [ 136 ].…”

Section: Epigenetic Modifiers As Therapeutic Adjuvants For Melanoma Patientsmentioning

confidence: 99%

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

Gracia-Hernandez

Munoz

Villagra

2021

Cancers

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Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.

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DNA methylation and histone acetylation regulate the expression of MGMT and chemosensitivity to temozolomide in malignant melanoma cell lines

Cited by 21 publications

References 26 publications

Epigenetic modulation of BRCA‐1 and MGMT genes, and histones H4 and H3 are associated with breast tumors

Epigenetic modulation of BRCA‐1 and MGMT genes, and histones H4 and H3 are associated with breast tumors

Tanshinone IIA induces apoptosis via inhibition of Wnt/β-catenin/MGMT signaling in AtT-20 cells

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

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