Polycomb repressor complex-2 is a novel target for mesothelioma therapy

Clinton D. Kemp, Mahadev Rao, Sichuan Xi, Suzanne Inchauste, Haresh Mani, Patricia Fetsch, Armando Filie, Mary Zhang, Julie A. Hong, Robert L. Walker, Yuelin J. Zhu, R. Taylor Ripley, Aarti Mathur, Fang Liu, Maocheng Yang, Paul A. Meltzer, Victor E. Marquez, Assunta De Rienzo, Raphael Bueno, David S. Schrump

Research output: Contribution to journalArticle

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Abstract

Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 or EED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.

Original languageEnglish
Pages (from-to)77-90
Number of pages14
JournalClinical Cancer Research
Volume18
Issue number1
DOIs
Publication statusPublished - 01-01-2012

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Mesothelioma
Polycomb-Group Proteins
Reverse Transcriptase Polymerase Chain Reaction
Transcriptome
Therapeutics
Pleura
Heterografts
Epigenomics
Small Interfering RNA
Agar
Malignant Mesothelioma
Research Design
Stem Cells
Cell Count
Immunohistochemistry
Survival
3-deazaneplanocin
Neoplasms

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Kemp, C. D., Rao, M., Xi, S., Inchauste, S., Mani, H., Fetsch, P., ... Schrump, D. S. (2012). Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clinical Cancer Research, 18(1), 77-90. https://doi.org/10.1158/1078-0432.CCR-11-0962
Kemp, Clinton D. ; Rao, Mahadev ; Xi, Sichuan ; Inchauste, Suzanne ; Mani, Haresh ; Fetsch, Patricia ; Filie, Armando ; Zhang, Mary ; Hong, Julie A. ; Walker, Robert L. ; Zhu, Yuelin J. ; Taylor Ripley, R. ; Mathur, Aarti ; Liu, Fang ; Yang, Maocheng ; Meltzer, Paul A. ; Marquez, Victor E. ; De Rienzo, Assunta ; Bueno, Raphael ; Schrump, David S. / Polycomb repressor complex-2 is a novel target for mesothelioma therapy. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 1. pp. 77-90.
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abstract = "Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85{\%} of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 or EED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.",
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Kemp, CD, Rao, M, Xi, S, Inchauste, S, Mani, H, Fetsch, P, Filie, A, Zhang, M, Hong, JA, Walker, RL, Zhu, YJ, Taylor Ripley, R, Mathur, A, Liu, F, Yang, M, Meltzer, PA, Marquez, VE, De Rienzo, A, Bueno, R & Schrump, DS 2012, 'Polycomb repressor complex-2 is a novel target for mesothelioma therapy', Clinical Cancer Research, vol. 18, no. 1, pp. 77-90. https://doi.org/10.1158/1078-0432.CCR-11-0962

Polycomb repressor complex-2 is a novel target for mesothelioma therapy. / Kemp, Clinton D.; Rao, Mahadev; Xi, Sichuan; Inchauste, Suzanne; Mani, Haresh; Fetsch, Patricia; Filie, Armando; Zhang, Mary; Hong, Julie A.; Walker, Robert L.; Zhu, Yuelin J.; Taylor Ripley, R.; Mathur, Aarti; Liu, Fang; Yang, Maocheng; Meltzer, Paul A.; Marquez, Victor E.; De Rienzo, Assunta; Bueno, Raphael; Schrump, David S.

In: Clinical Cancer Research, Vol. 18, No. 1, 01.01.2012, p. 77-90.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Polycomb repressor complex-2 is a novel target for mesothelioma therapy

AU - Kemp, Clinton D.

AU - Rao, Mahadev

AU - Xi, Sichuan

AU - Inchauste, Suzanne

AU - Mani, Haresh

AU - Fetsch, Patricia

AU - Filie, Armando

AU - Zhang, Mary

AU - Hong, Julie A.

AU - Walker, Robert L.

AU - Zhu, Yuelin J.

AU - Taylor Ripley, R.

AU - Mathur, Aarti

AU - Liu, Fang

AU - Yang, Maocheng

AU - Meltzer, Paul A.

AU - Marquez, Victor E.

AU - De Rienzo, Assunta

AU - Bueno, Raphael

AU - Schrump, David S.

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 or EED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.

AB - Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 or EED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.

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