Phospholipase c delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer

X. T. Hu; F. B. Zhang; Y. C. Fan; X. S. Shu; A. H.Y. Wong; W. Zhou; Q. L. Shi; H. M. Tang; L. Fu; X. Y. Guan; S. Y. Rha; Q. Tao; C. He

doi:10.1038/onc.2009.92

Phospholipase c delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer

X. T. Hu, F. B. Zhang, Y. C. Fan, X. S. Shu, A. H.Y. Wong, W. Zhou, Q. L. Shi, H. M. Tang, L. Fu, X. Y. Guan, S. Y. Rha, Q. Tao, C. He

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

56 Citations (Scopus)

Abstract

Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2′-deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.

Original language	English
Pages (from-to)	2466-2475
Number of pages	10
Journal	Oncogene
Volume	28
Issue number	26
DOIs	https://doi.org/10.1038/onc.2009.92
Publication status	Published - 2009 Jul 2

Bibliographical note

Funding Information:
This study was supported by a grant from the Chinese University of Hong Kong, a grant from National Natural Science Foundation of China (Grant no. 30770920/ C03030202) and a grant from Natural Science Foundation of Zhejiang Province (Grant no. Y206090).

All Science Journal Classification (ASJC) codes

Molecular Biology
Genetics
Cancer Research

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10.1038/onc.2009.92

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Hu, X. T., Zhang, F. B., Fan, Y. C., Shu, X. S., Wong, A. H. Y., Zhou, W., Shi, Q. L., Tang, H. M., Fu, L., Guan, X. Y., Rha, S. Y., Tao, Q., & He, C. (2009). Phospholipase c delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene, 28(26), 2466-2475. https://doi.org/10.1038/onc.2009.92

@article{cf4804e0c08942ccaf668456d05ea2bc,

title = "Phospholipase c delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer",

abstract = "Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2′-deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.",

author = "Hu, {X. T.} and Zhang, {F. B.} and Fan, {Y. C.} and Shu, {X. S.} and Wong, {A. H.Y.} and W. Zhou and Shi, {Q. L.} and Tang, {H. M.} and L. Fu and Guan, {X. Y.} and Rha, {S. Y.} and Q. Tao and C. He",

note = "Funding Information: This study was supported by a grant from the Chinese University of Hong Kong, a grant from National Natural Science Foundation of China (Grant no. 30770920/ C03030202) and a grant from Natural Science Foundation of Zhejiang Province (Grant no. Y206090).",

year = "2009",

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doi = "10.1038/onc.2009.92",

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Hu, XT, Zhang, FB, Fan, YC, Shu, XS, Wong, AHY, Zhou, W, Shi, QL, Tang, HM, Fu, L, Guan, XY, Rha, SY, Tao, Q & He, C 2009, 'Phospholipase c delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer', Oncogene, vol. 28, no. 26, pp. 2466-2475. https://doi.org/10.1038/onc.2009.92

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AU - Hu, X. T.

AU - Zhang, F. B.

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AU - Shu, X. S.

AU - Wong, A. H.Y.

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AU - Shi, Q. L.

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AU - Guan, X. Y.

AU - Rha, S. Y.

AU - Tao, Q.

AU - He, C.

N1 - Funding Information: This study was supported by a grant from the Chinese University of Hong Kong, a grant from National Natural Science Foundation of China (Grant no. 30770920/ C03030202) and a grant from Natural Science Foundation of Zhejiang Province (Grant no. Y206090).

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N2 - Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2′-deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.

AB - Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2′-deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.

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Phospholipase c delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer

Abstract

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