Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

Silverman, Brittany; Shi, Jiaqi

doi:10.3390/ijms17122138

Cited by 27 publications

(32 citation statements)

References 132 publications

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“…The epigenetic hypermethylation of the promoter CpG islands of tumor-suppressor genes, including APC, BRCA1, p16 INK4a can induce transcription inactivation during tumorigenesis, which is often observed in pancreatic cancer (6). Previous studies in pancreatic cancer reported frequent genetic abnormalities in Kras gene activation, but also in the epigenetic inactivation of p16 INK4a , p53 and SMAD4 in >50% of pancreatic ductal cancer cases (4,5).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, somatic mutations in the tumor protein p53 (TP53), SMAD family member 4 (SMAD4) and p16 genes can also contribute to the progression of pancreatic cancer (3)(4)(5). In addition to genetic mutations, modifications that are not due to changes in DNA sequence, including promoter hypermethylation, are often observed in pancreatic cancer cells (6). Epigenetic silencing and transcriptional inactivation due to hypermethylation in the 5'promoter regions of specific genes, including tumor-suppressor genes, for example hMLH1, BRCA1, p16 INK4a , can contribute to cancer progression (7).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

et al. 2020

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No difference in the gene methylation status of tumor-suppression genes between pancreatic cancer tissues and adjacent non-cancer tissues is observed. The present study investigated whether the promoter CpG islands of the cysteine dioxygenase 1 (CDO1), tachykinin precursor 1 (TAC1) and checkpoint with forkhead and ring finger domains (CHFR) genes were methylated in pancreatic cancer and adjacent non-cancerous pancreatic tissue in order to determine if they could be considered as markers for the detection of pancreatic cancer. A total of 38 Formalin-fixed and paraffin-embedded pancreatic adenocarcinoma tissues and their adjacent non-cancerous specimens from patients with pancreatic cancer, as well as 9 non-cancerous pancreatic samples from patients without pancreatic adenocarcinoma were obtained following surgical resection. The hypermethylation of CpG islands was detected using a methylation-specific quantitative PCR. The methylation values were calculated using the ∆Cq method and were expressed as 2-ΔCq. The 2-ΔCq value of the CDO1 promoter from pancreatic adenocarcinoma specimens was significantly higher compared with that of adjacent non-cancerous and tumor-free pancreatic tissues (P<0.0001 and P= 0.0008, respectively). The 2-ΔCq value of the TAC1 promoter of pancreatic adenocarcinoma was also significantly higher compared with that of adjacent non-cancerous tissues and tumor-free pancreatic samples (both P<0.0001). However, there was no significant difference in the 2-ΔCq value of the CHFR promoter among the pancreatic cancer, adjacent non-cancer tissue and tumor-free pancreatic samples. Furthermore, 12 out of the 38 pancreatic adenocarcinoma cases (31.6%) presented some methylation in the CHFR promoter. The results from Kaplan-Meier analysis between CHFR promoter methylation values and the clinicopathological characteristics of patients with pancreatic adenocarcinoma demonstrated that CHFR promoter methylation was significantly associated with lymph node metastasis. The methylation values of CDO1 and TAC1 promoters in cancer tissues were higher compared with adjacent tissues. However, whether hypermethylation of CDO1 and TAC1 promoters may serve as a biomarker in the diagnosis of pancreatic adenocarcinoma remains unclear.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

et al. 2020

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“…Interestingly, recent studies demonstrate that dysregulation of epigenetic regulators is essential for PDAC progression as well as for that of many other tumors [9]. Genomic deletions, mutations, and rearrangements frequently target genes encoding components of the chromatin remodeling complex (SWI/SNF), which have been identified in 10-15% of PDAC patients [10].…”

Section: Pdac From Genetics To Epigeneticsmentioning

confidence: 99%

“…The methylation of tumor suppressor genes is the best-characterized epigenetic event in several malignancies, including PDAC [11]. In fact, several genes such as APC, BRCA1, P16INK4a, P15INK4b, RARβ, and p73 are frequently methylated [10]. Recent studies have revealed that apparent DNA methylation occurred in critical signaling pathways in PDAC such as TGFβ, WNT, integrin, cell adhesion, and axon guidance signaling pathways [35].…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetics: Dissecting Gene Expression Alteration in PDAC

Abukiwan¹,

Berger²

2019

DNA Repair- An Update

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Pancreatic cancer is the fourth leading cause of cancer deaths, with a low 5-year survival rate of about 7% due to its highly invasive nature. Pancreatic ductal adenocarcinoma (PDAC) comprises more than 90% of all pancreatic cancer cases. At the time of detection, around 80% of cases harbor metastases due to the lack of early diagnosis. For decades, scientists have primarily focused on dissecting the origin of pancreatic cancer through genetic alterations and their contribution to diagnosis. Recently, PDAC research has turned into epigenetics to revolutionize our understanding about the silencing of critical regulatory genes. Epigenetic events can be divided mechanistically into various components, including DNA methylation, histone posttranslational modification, nucleosome remodeling, and regulation of transcription or translation by microRNA. The identified epigenetic processes in PDAC contribute to its specific epigenotype and are correlated phenotypic features. Strikingly, some of them have been suggested to have potential as cancer biomarkers, for disease monitoring, prognosis, and risk validation. As epigenetic aberrations are reversible, their correction will become as a promising therapeutic target.

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“…Numerous reviews have deeply discussed and extensively summarized the recent advances of targeting epigenetics in cancer, in general, as well as in pancreatic cancer in particular [3,9,[16][17][18][19][20][21]. In this review, we focus on the transcriptional mechanisms of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal (BET) and Histone Deacetylase (HDAC) inhibitors, which represent promising therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Targeting of Aberrant Transcriptional Modulation in Pancreatic Cancer

Hamdan

Johnsen

2018

Epigenomes

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While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and Forkhead Box A1 (FOXA1), rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner.

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Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

Cited by 27 publications

References 132 publications

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

Epigenetics: Dissecting Gene Expression Alteration in PDAC

Epigenetic Targeting of Aberrant Transcriptional Modulation in Pancreatic Cancer

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