Methylation of tumor suppressor gene CDH13 and SHP1 promoters and their epigenetic regulation by the UHRF1/PRMT5 complex in endometrial carcinoma

Yan, Sheng; Wang, Hongtao; Liu, Dongchen; Zhang, Cheng; Deng, Yupeng; Yang, Fan; Zhang, Tingguo; Zhang, Cuijuan

doi:10.1016/j.ygyno.2015.11.017

Cited by 48 publications

(42 citation statements)

References 35 publications

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“…A high frequency of promoter hypermethylation was also observed in endometrial carcinoma, and was identified to be associated with patient age and tumor differentiation. PTPN6 promoters were completely methylated in endometrial carcinoma cell lines, and this methylation status was reversed by 5-Aza-dC treatment (25). In the present study, downregulation of PTPN6 was detected in esophageal cancer cell lines and ESCC tissues, and P2 hypermethylation may be one of the important epigenetic mechanisms silencing this gene in ESCC.…”

Section: Discussionsupporting

confidence: 56%

Aberrant promoter�2 methylation‑mediated downregulation of protein tyrosine phosphatase, non‑receptor type�6, is associated with progression of esophageal squamous cell carcinoma

et al. 2019

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The human protein tyrosine phosphatase, nonreceptor type 6 (PTPN6) gene is located on chromosome 12p13 and encodes an Mr 68,000 non-receptor type protein-tyrosine phosphatase. The PTPN6 gene has been considered as a candidate tumor suppressor in hematological and solid malignancies, and promoter methylation may be an epigenetic modification silencing its expression. However, the detailed role of PTPN6 and its promoter methylation status in the pathogenesis of esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. The aim of the present study was to investigate PTPN6 expression in ESCC tissues and esophageal cancer cell lines, detect the effect of CpG hypermethylation on the activity of PTPN6, and additionally elucidate the role and prognostic significance of PTPN6 in ESCC tumorigenesis and progression. The expression of PTPN6 was identified to be significantly downregulated in esophageal cancer cell lines and ESCC tissues. Marked upregulation of PTPN6 was detected in 5-aza-2'-deoxycytidine-treated esophageal cancer cells, and frequent hypermethylation of the CpG sites within the P2 promoter (P2) was detected in ESCC tissues and esophageal cancer cell lines. The expression and methylation status of PTPN6 was associated with tumor node metastasis stage, pathological differentiation and lymph node metastasis in patients with ESCC. Aberrant hypermethylation of the P2 exhibited marked tumor specificity and was identified to be associated with the expression level of PTPN6. Downregulation and hypermethylation of PTPN6 were identified to be associated with poor ESCC patient survival. Furthermore, upregulation of PTPN6 inhibited the proliferation and invasion of esophageal cancer cells in vitro. The results of the present study suggest that PTPN6 may serve as a tumor suppressor in ESCC, and it may serve as a potential target for antitumor therapy.Abbreviations: P2, promoter 2; ESCC, esophageal squamous cell carcinoma; PTPs, protein tyrosine phosphatases; PTPN6, protein tyrosine phosphatase, non-receptor type 6

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Section: Discussionsupporting

confidence: 56%

Aberrant promoter�2 methylation‑mediated downregulation of protein tyrosine phosphatase, non‑receptor type�6, is associated with progression of esophageal squamous cell carcinoma

et al. 2019

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“…Involved in large-scale reorganization of heterochromatin Meng et al 52 Protein arginine methyltransferase 5 (PRMT5) catalyzes dimethylation of H3R8 (repressive mark) Sheng et al 53 gastric cancer cells resulted in reactivation of seven tumor suppressor genes (CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML) by promoter demethylation and inhibited cell proliferation. 9 Knockdown of UHRF1 in A549 lung adenocarcinoma cells led to hypomethylation of otherwise frequently hypermethylated RASSF1, CYGB, and CDH13 tumor suppressor genes.…”

Section: F-box Protein Which Plays An Important Role In Regulating Ubmentioning

confidence: 99%

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Sidhu

Capalash

2017

Tumour Biol.

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UHRF1 is a master regulator of epigenome as it coordinates DNA methylation and histone modifications. Compelling evidence suggests a strong link between UHRF1 overexpression and tumorigenesis, substantiating its ability to act as a potential biomarker for cancer diagnosis and prognosis. UHRF1 also mediates repair of damaged DNA that makes cancer cells resistant toward cytocidal drugs. Hence, understanding the molecular mechanism of UHRF1 regulation would help in developing cancer therapeutics. Natural compounds have shown applicability to downregulate UHRF1 leading to growth arrest and apoptosis in cancer cells.

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“…For instance, UHRF1 has been shown to recruit histone lysine methyltransferase G9a to the BRCA1 promoter and with subsequent histone 3 lysine 9 methylation [42]. In another study, it has been reported that UHRF1 associates with PRMT5 (Protein arginine N-methyltransferase 5) in endometrial carcinoma [44]. In the same study, it has been shown that the promoters of TSGs CH13 and SHP1 were hypermethylated but whether there is a link between the activity of PRMT5 and TSGs silencing still remains elusive.…”

Section: Role Of Uhrf1 In the Epigenetic Silencing Of Tsgs In Cancermentioning

confidence: 99%

“…UHRF1 downregulation and p16 INK4A upregulation [32]. Although, several studies [37, 44, 108, 109] tend to show that reactivation of tumor suppressor gene involves a UHRF1 downregulation-dependent promoter demethylation, the contribution of other mechanisms are not excluded. Indeed, UHRF1 has been suggested to be a main player in the reactivation of the tumor suppressor gene Pax1 (Paired box gene1) in several cancer cell lines in response to curcumin and resveratrol through a mechanism involving histone methylation and deacetylation rather than a DNA methylation-dependent process [110].…”

Section: Signalling Pathways Involved In Uhrf1 Regulation In Cancer Cmentioning

confidence: 99%

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

Alhosin

Omran

Zamzami

et al. 2016

J Exp Clin Cancer Res

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Epigenetic silencing of tumor suppressor genes (TSGs) through DNA methylation and histone changes is a main hallmark of cancer. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a potent oncogene overexpressed in various solid and haematological tumors and its high expression levels are associated with decreased expression of several TSGs including p16 INK4A, BRCA1, PPARG and KiSS1. Using its several functional domains, UHRF1 creates a strong coordinated dialogue between DNA methylation and histone post-translation modification changes causing the epigenetic silencing of TSGs which allows cancer cells to escape apoptosis. To ensure the silencing of TSGs during cell division, UHRF1 recruits several enzymes including histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1) and histone lysine methyltransferases G9a and Suv39H1 to the right place at the right moment. Several in vitro and in vivo works have reported the direct implication of the epigenetic player UHRF1 in tumorigenesis through the repression of TSGs expression and suggested UHRF1 as a promising target for cancer treatment. This review describes the molecular mechanisms underlying UHRF1 regulation in cancer and discusses its importance as a therapeutic target to induce the reactivation of TSGs and subsequent apoptosis.

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Methylation of tumor suppressor gene CDH13 and SHP1 promoters and their epigenetic regulation by the UHRF1/PRMT5 complex in endometrial carcinoma

Cited by 48 publications

References 35 publications

Aberrant promoter�2 methylation‑mediated downregulation of protein tyrosine phosphatase, non‑receptor type�6, is associated with progression of esophageal squamous cell carcinoma

Aberrant promoter�2 methylation‑mediated downregulation of protein tyrosine phosphatase, non‑receptor type�6, is associated with progression of esophageal squamous cell carcinoma

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

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