Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy

Jacob, Samson T.; Motiwala, Tasneem

doi:10.1038/sj.cgt.7700828

Cited by 56 publications

(52 citation statements)

References 67 publications

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“…Furthermore, the effect of PTPROt expression on the action of fludarabine also opens up a new avenue to explore combination therapy with epigenetic drugs, especially in resilient cases in which PTPROt is suppressed. It is interesting that most classical protein tyrosine phosphatases harbor a CpG island (31). Although methylation of only a few protein tyrosine phosphatases has been reported in human cancer (see refs.…”

Section: Discussionmentioning

confidence: 99%

Methylation and Silencing of Protein Tyrosine Phosphatase Receptor Type O in Chronic Lymphocytic Leukemia

Motiwala

Majumder

Kutay

et al. 2007

Clinical Cancer Research

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Purpose: Previous studies in our laboratory have shown the progressive methylation and suppression of the gene encoding protein tyrosine phosphatase, PTPRO, in the livers of rats fed a methyl-deficient diet that induces hepatocarcinogenesis. Subsequently, we observed the methylation of PTPRO in primary human lung tumors and also showed its potential tumor suppressor characteristics. The present study was undertaken to investigate whether the truncated form of PTPRO (PTPROt), specifically expressed in naI« ve B lymphocytes, was also methylated and suppressed in chronic lymphocytic leukemia (CLL), a disease generally affecting B lymphocytes. Experimental Design and Results: Initial screening showed that 60% of the 52 CLL samples analyzed using methylation-specific PCR assay were methylated compared with B lymphocytes from normal individuals, which were not methylated. The expression of PTPROt, as measured by semiquantitative reverse transcription-PCR, inversely correlated with methylation in the few samples tested. Analysis of additional samples (n = 50) by combined bisulfite restriction analysis showed that the PTPRO CpG island was methylated in 82% of patients with CLL compared with B lymphocytes from normal individuals. Furthermore, overall expression of PTPRO was reduced in CLL relative to normal lymphocytes. The PTPRO gene was also suppressed by methylation in the CLL cell lineWaC3CD5, where it could be reactivated upon treatment with the DNA hypomethylating agent 5-AzaC. Ectopic expression of PTPROt in a nonexpressing cell line increased growth inhibition with fludarabine treatment, a therapy commonly used for CLL. Conclusion: This study reveals the potential role of PTPRO methylation and silencing in CLL tumorigenesis and also provides a novel molecular target in the epigenetic therapy.

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Section: Discussionmentioning

confidence: 99%

Methylation and Silencing of Protein Tyrosine Phosphatase Receptor Type O in Chronic Lymphocytic Leukemia

Motiwala

Majumder

Kutay

et al. 2007

Clinical Cancer Research

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“…This critical function of PTPs is involved in numerous intracellular signaling events that serve various biological behaviors, such as cell proliferation, differentiation, apoptosis, and so forth. 3,4 Recently, an accumulation of evidence has enriched the understanding of cancer biology, and it has been observed that PTPRO exhibits important …”

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confidence: 99%

Estrogen-Sensitive PTPRO Expression Represses Hepatocellular Carcinoma Progression by Control of STAT3

Hou

Jiang

et al. 2013

Hepatology

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Protein tyrosine phosphatase receptor type O (PTPRO), one of the receptor types of phosphotyrosine phosphatases (PTP), was recently described as a tumor suppressor in various kinds of cancers. We aimed to clarify the role of PTPRO in hepatocellular carcinoma (HCC). It was demonstrated in 180 pairs (120 male and 60 female) of clinical HCC specimens that the PTPRO level was significantly reduced, as compared with adjacent tissue, and the PTPRO level in male adjacent tissue was lower than in female. We further found that estrogen receptor alpha (ERα) could up-regulate PTPRO expression as a transcription factor. Moreover, an in vitro study showed that cell proliferation was inhibited and apoptosis was promoted in PTPRO-transduced HCC cell lines, whereas an in vivo study represented that tumor number and size was increased in ptpro −/− mice. As a result of its tumor-suppressive position, PTPRO was proved to down-regulate signal transducers and activators of transcription (STAT3) activity dependent on Janus kinase 2 (JAK2) and phosphoinositide 3-kinase (PI3K) dephosphorylation. Conclusions: PTPRO expression results in pathological deficiency and gender bias in HCC, which could be attributed to ERα regulation. The suppressive role of PTPRO in HCC could be ascribed to STAT3 inactivation.

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“…4 Gene expression of AXL has been correlated with DNA methylation levels in an Sp1/Sp3 transcription factor binding site in the promoter, suggesting DNA methylation plays a key role in determining gene function. 5,6 CpG methylation at this site has been reported to have high heritability. 7 Recent evidence also suggests AXL is an imprinted gene whose expression is maternally transmitted in some but not all individuals and dependent on DNA methylation in the locus.…”

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confidence: 99%

Heritability and role for the environment in DNA methylation in AXL receptor tyrosine kinase

2011

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Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy

Cited by 56 publications

References 67 publications

Methylation and Silencing of Protein Tyrosine Phosphatase Receptor Type O in Chronic Lymphocytic Leukemia

Methylation and Silencing of Protein Tyrosine Phosphatase Receptor Type O in Chronic Lymphocytic Leukemia

Estrogen-Sensitive PTPRO Expression Represses Hepatocellular Carcinoma Progression by Control of STAT3

Heritability and role for the environment in DNA methylation in AXL receptor tyrosine kinase

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