Conference Paper: Epigenetic silencing of the receptor tyrosine phosphatase, PTPRK, located at the frequently deleted 6q22.33-q23.2 region, leads to tumor growth via the constitutive activation of STAT3 in nasal-type NK/T-cell lymphoma

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Title	Epigenetic silencing of the receptor tyrosine phosphatase, PTPRK, located at the frequently deleted 6q22.33-q23.2 region, leads to tumor growth via the constitutive activation of STAT3 in nasal-type NK/T-cell lymphoma
Authors	Chen, YW Guo, T Shen, L Wong, KY Au, WY Tao, Q Wong, LY Tang, CO Choi, WL Liu, WP Li, GD Shimizu, N Tsuchiyama, J Loong, F Liang, R Kwong, YL Srivastava, G
Issue Date	2011
Publisher	American Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation	The 53rd Annual Meeting and Exposition of the American Society of Hematology (ASH 2011), San Diego, CA., 10-13 December 2011. In Blood, 2011, v. 118 n. 21, abstract 1378 [How to Cite?]
Abstract	Tumorigenesis is a multi-step process and involves the silencing of tumor suppressor genes (TSGs) by genetic and/or epigenetic mechanisms. Aberrant hypermethylation of gene promoters is a major epigenetic mechanism associated with TSG silencing in cancer. To identify putative TSGs that might be epigenetically silenced in extranodal NK/T-cell lymphoma, nasal type (ENKL), a genome-wide screening was performed in a commonly deleted region 6q22.33-q23.2. PTPRK (protein tyrosine phosphatase, receptor type, kappa) was identified as the only gene out of 77 genes mapped to the 6q22.33-q23.2 region that was upregulated in four of five ENKL cell lines after treatment with the demethylation agent 5-aza-2' deoxycytidine (5-aza-dC). Further analysis by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) confirmed that the CpG island surrounding the transcriptional start site of PTPRK was methylated in ENKL cell lines not expressing PTPRK. Similarly, a significant correlation between methylation of the PTPRK promoter and downregulation of PTPRK mRNA and protein expression (p=0.019 and p=0.048, respectively) was detected in 39 primary ENKLs. PTPRK gene allelic loss was detected in 80% of cell lines and 47% of primary ENKLs. Functional analyses by in vitro assays showed that the re-expression of PTPRK by retroviral transduction in the PTPRK non-expressing NKYS cell line suppressed the size and number of colonies formed, led to a remarkable increase in the apoptotic cell population and cell cycle arrest at G0/G1 phase. Moreover, PTPRK re-expression substantially reduced the migration and invasion of NKYS cells. Conversely, the inhibitory effect of PTPRK was significantly decreased by partial shRNA knockdown of PTPRK expression in the PTPRK-expressing SNK-6 cell line. The re-expression of PTPRK in another PTPRK non-expressing YT cell line suppressed tumor growth and metastasis in a nude mouse xenograft model. Consistent with these in vitro and in vivo findings, clinicopathological correlation analysis showed that PTPRK silencing was detected mostly in the ENKL patients with advanced and metastatic disease. Examination of the PTPRK protein sequence revealed that the cytoplasmic domain possesses a consensus STAT3 binding domain (YXXQ). Re-expression of PTPRK in NKYS cells resulted in a significant decrease in the level of phospho-STAT3 (Tyr705), whereas PTPRK knockdown in SNK-6 cells resulted in an increased level of phospho-STAT3 (Tyr705). These data suggested that PTPRK dephosphorylates and regulates the oncoprotein STAT3. Overall, this study shows that PTPRK is a putative TSG in the 6q22.33-q23.2 region that is frequently deleted and epigenetically silenced in ENKL, and the loss of PTPRK expression promotes tumor growth via the aberrant constitutive activation of STAT3 in ENKL. Specific therapies aimed at targeting STAT3 warrants further exploration.
Description	Open Access Journal This journal issue is proceedings of ASH Conference 2011 Poster Sessions - 603. Oncogenes and Tumor Suppressors: Poster I
ISSN	0006-4971 2011 Impact Factor: 9.898 2011 SCImago Journal Rankings: 1.698

DC Field	Value
dc.contributor.author	Chen, YW
dc.contributor.author	Guo, T
dc.contributor.author	Shen, L
dc.contributor.author	Wong, KY
dc.contributor.author	Au, WY
dc.contributor.author	Tao, Q
dc.contributor.author	Wong, LY
dc.contributor.author	Tang, CO
dc.contributor.author	Choi, WL
dc.contributor.author	Liu, WP
dc.contributor.author	Li, GD
dc.contributor.author	Shimizu, N
dc.contributor.author	Tsuchiyama, J
dc.contributor.author	Loong, F
dc.contributor.author	Liang, R
dc.contributor.author	Kwong, YL
dc.contributor.author	Srivastava, G
dc.date.accessioned	2012-08-16T06:08:00Z
dc.date.available	2012-08-16T06:08:00Z
dc.date.issued	2011
dc.description.abstract	Tumorigenesis is a multi-step process and involves the silencing of tumor suppressor genes (TSGs) by genetic and/or epigenetic mechanisms. Aberrant hypermethylation of gene promoters is a major epigenetic mechanism associated with TSG silencing in cancer. To identify putative TSGs that might be epigenetically silenced in extranodal NK/T-cell lymphoma, nasal type (ENKL), a genome-wide screening was performed in a commonly deleted region 6q22.33-q23.2. PTPRK (protein tyrosine phosphatase, receptor type, kappa) was identified as the only gene out of 77 genes mapped to the 6q22.33-q23.2 region that was upregulated in four of five ENKL cell lines after treatment with the demethylation agent 5-aza-2' deoxycytidine (5-aza-dC). Further analysis by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) confirmed that the CpG island surrounding the transcriptional start site of PTPRK was methylated in ENKL cell lines not expressing PTPRK. Similarly, a significant correlation between methylation of the PTPRK promoter and downregulation of PTPRK mRNA and protein expression (p=0.019 and p=0.048, respectively) was detected in 39 primary ENKLs. PTPRK gene allelic loss was detected in 80% of cell lines and 47% of primary ENKLs. Functional analyses by in vitro assays showed that the re-expression of PTPRK by retroviral transduction in the PTPRK non-expressing NKYS cell line suppressed the size and number of colonies formed, led to a remarkable increase in the apoptotic cell population and cell cycle arrest at G0/G1 phase. Moreover, PTPRK re-expression substantially reduced the migration and invasion of NKYS cells. Conversely, the inhibitory effect of PTPRK was significantly decreased by partial shRNA knockdown of PTPRK expression in the PTPRK-expressing SNK-6 cell line. The re-expression of PTPRK in another PTPRK non-expressing YT cell line suppressed tumor growth and metastasis in a nude mouse xenograft model. Consistent with these in vitro and in vivo findings, clinicopathological correlation analysis showed that PTPRK silencing was detected mostly in the ENKL patients with advanced and metastatic disease. Examination of the PTPRK protein sequence revealed that the cytoplasmic domain possesses a consensus STAT3 binding domain (YXXQ). Re-expression of PTPRK in NKYS cells resulted in a significant decrease in the level of phospho-STAT3 (Tyr705), whereas PTPRK knockdown in SNK-6 cells resulted in an increased level of phospho-STAT3 (Tyr705). These data suggested that PTPRK dephosphorylates and regulates the oncoprotein STAT3. Overall, this study shows that PTPRK is a putative TSG in the 6q22.33-q23.2 region that is frequently deleted and epigenetically silenced in ENKL, and the loss of PTPRK expression promotes tumor growth via the aberrant constitutive activation of STAT3 in ENKL. Specific therapies aimed at targeting STAT3 warrants further exploration.
dc.description.nature	link_to_OA_fulltext
dc.description	Open Access Journal
dc.description	This journal issue is proceedings of ASH Conference 2011
dc.description	Poster Sessions - 603. Oncogenes and Tumor Suppressors: Poster I
dc.identifier.citation	The 53rd Annual Meeting and Exposition of the American Society of Hematology (ASH 2011), San Diego, CA., 10-13 December 2011. In Blood, 2011, v. 118 n. 21, abstract 1378 [How to Cite?]
dc.identifier.hkuros	203851
dc.identifier.issn	0006-4971 2011 Impact Factor: 9.898 2011 SCImago Journal Rankings: 1.698
dc.identifier.issue	21
dc.identifier.uri	http://hdl.handle.net/10722/160323
dc.identifier.volume	118
dc.language	eng
dc.publisher	American Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
dc.publisher.place	United States
dc.relation.ispartof	Blood
dc.title	Epigenetic silencing of the receptor tyrosine phosphatase, PTPRK, located at the frequently deleted 6q22.33-q23.2 region, leads to tumor growth via the constitutive activation of STAT3 in nasal-type NK/T-cell lymphoma
dc.type	Conference_Paper

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PTPRK (protein tyrosine phosphatase, receptor type, kappa) was identified as the only gene out of 77 genes mapped to the 6q22.33-q23.2 region that was upregulated in four of five ENKL cell lines after treatment with the demethylation agent 5-aza-2&apos; deoxycytidine (5-aza-dC). Further analysis by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) confirmed that the CpG island surrounding the transcriptional start site of PTPRK was methylated in ENKL cell lines not expressing PTPRK. Similarly, a significant correlation between methylation of the PTPRK promoter and downregulation of PTPRK mRNA and protein expression (p=0.019 and p=0.048, respectively) was detected in 39 primary ENKLs. PTPRK gene allelic loss was detected in 80% of cell lines and 47% of primary ENKLs. Functional analyses by in vitro assays showed that the re-expression of PTPRK by retroviral transduction in the PTPRK non-expressing NKYS cell line suppressed the size and number of colonies formed, led to a remarkable increase in the apoptotic cell population and cell cycle arrest at G0/G1 phase. Moreover, PTPRK re-expression substantially reduced the migration and invasion of NKYS cells. Conversely, the inhibitory effect of PTPRK was significantly decreased by partial shRNA knockdown of PTPRK expression in the PTPRK-expressing SNK-6 cell line. The re-expression of PTPRK in another PTPRK non-expressing YT cell line suppressed tumor growth and metastasis in a nude mouse xenograft model. Consistent with these in vitro and in vivo findings, clinicopathological correlation analysis showed that PTPRK silencing was detected mostly in the ENKL patients with advanced and metastatic disease. Examination of the PTPRK protein sequence revealed that the cytoplasmic domain possesses a consensus STAT3 binding domain (YXXQ). Re-expression of PTPRK in NKYS cells resulted in a significant decrease in the level of phospho-STAT3 (Tyr705), whereas PTPRK knockdown in SNK-6 cells resulted in an increased level of phospho-STAT3 (Tyr705). These data suggested that PTPRK dephosphorylates and regulates the oncoprotein STAT3. Overall, this study shows that PTPRK is a putative TSG in the 6q22.33-q23.2 region that is frequently deleted and epigenetically silenced in ENKL, and the loss of PTPRK expression promotes tumor growth via the aberrant constitutive activation of STAT3 in ENKL. Specific therapies aimed at targeting STAT3 warrants further exploration.</description.abstract><language>eng</language><publisher>American Society of Hematology. 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