γ-catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth

Robert A. Winn, Roy M. Bremnes, Lynne T Bemis, Wilbur A. Franklin, York E. Miller, Carlyne Cool, Lynn E. Heasley

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that β-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, γ-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak γ-catenin staining in ∼ 30% of the specimens. Treatment of NSCLC cells expressing reduced γ-catenin protein with 5-aza-2′-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased γ-catenin protein content in NSCLC cells with low γ-catenin expression. Significantly, the activity of a β-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed γ-catenin relative to those lines that highly expressed γ-catenin. Moreover, transfection of these cells with a γ-catenin expression plasmid reduced the elevated TCF activity by 85% and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that γ-catenin can function as an inhibitor of β-catenin/TCF-dependent gene transcription and highlights γ-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.

Original languageEnglish (US)
Pages (from-to)7497-7506
Number of pages10
JournalOncogene
Volume21
Issue number49
DOIs
StatePublished - Oct 24 2002

Fingerprint

Catenins
Lung Neoplasms
Growth
decitabine
Cell Line
Neoplasms
trichostatin A
Tumor Suppressor Proteins
Wnt Signaling Pathway
Histone Deacetylase Inhibitors
DNA Methylation
Luciferases
Colonic Neoplasms
Plastics
Agar

Keywords

  • Cell transformation
  • Lung cancer
  • NSCLC
  • Tumor suppressor
  • γ-catenin

Cite this

γ-catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth. / Winn, Robert A.; Bremnes, Roy M.; Bemis, Lynne T; Franklin, Wilbur A.; Miller, York E.; Cool, Carlyne; Heasley, Lynn E.

In: Oncogene, Vol. 21, No. 49, 24.10.2002, p. 7497-7506.

Research output: Contribution to journalArticle

Winn, Robert A. ; Bremnes, Roy M. ; Bemis, Lynne T ; Franklin, Wilbur A. ; Miller, York E. ; Cool, Carlyne ; Heasley, Lynn E. / γ-catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth. In: Oncogene. 2002 ; Vol. 21, No. 49. pp. 7497-7506.
@article{ea9e6b8bd12848e5ad165165e71ec6a5,
title = "γ-catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth",
abstract = "Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that β-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, γ-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak γ-catenin staining in ∼ 30{\%} of the specimens. Treatment of NSCLC cells expressing reduced γ-catenin protein with 5-aza-2′-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased γ-catenin protein content in NSCLC cells with low γ-catenin expression. Significantly, the activity of a β-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed γ-catenin relative to those lines that highly expressed γ-catenin. Moreover, transfection of these cells with a γ-catenin expression plasmid reduced the elevated TCF activity by 85{\%} and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that γ-catenin can function as an inhibitor of β-catenin/TCF-dependent gene transcription and highlights γ-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.",
keywords = "Cell transformation, Lung cancer, NSCLC, Tumor suppressor, γ-catenin",
author = "Winn, {Robert A.} and Bremnes, {Roy M.} and Bemis, {Lynne T} and Franklin, {Wilbur A.} and Miller, {York E.} and Carlyne Cool and Heasley, {Lynn E.}",
year = "2002",
month = "10",
day = "24",
doi = "10.1038/sj.onc.1205963",
language = "English (US)",
volume = "21",
pages = "7497--7506",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "49",

}

TY - JOUR

T1 - γ-catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth

AU - Winn, Robert A.

AU - Bremnes, Roy M.

AU - Bemis, Lynne T

AU - Franklin, Wilbur A.

AU - Miller, York E.

AU - Cool, Carlyne

AU - Heasley, Lynn E.

PY - 2002/10/24

Y1 - 2002/10/24

N2 - Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that β-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, γ-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak γ-catenin staining in ∼ 30% of the specimens. Treatment of NSCLC cells expressing reduced γ-catenin protein with 5-aza-2′-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased γ-catenin protein content in NSCLC cells with low γ-catenin expression. Significantly, the activity of a β-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed γ-catenin relative to those lines that highly expressed γ-catenin. Moreover, transfection of these cells with a γ-catenin expression plasmid reduced the elevated TCF activity by 85% and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that γ-catenin can function as an inhibitor of β-catenin/TCF-dependent gene transcription and highlights γ-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.

AB - Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that β-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, γ-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak γ-catenin staining in ∼ 30% of the specimens. Treatment of NSCLC cells expressing reduced γ-catenin protein with 5-aza-2′-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased γ-catenin protein content in NSCLC cells with low γ-catenin expression. Significantly, the activity of a β-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed γ-catenin relative to those lines that highly expressed γ-catenin. Moreover, transfection of these cells with a γ-catenin expression plasmid reduced the elevated TCF activity by 85% and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that γ-catenin can function as an inhibitor of β-catenin/TCF-dependent gene transcription and highlights γ-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.

KW - Cell transformation

KW - Lung cancer

KW - NSCLC

KW - Tumor suppressor

KW - γ-catenin

UR - http://www.scopus.com/inward/record.url?scp=0037168193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037168193&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1205963

DO - 10.1038/sj.onc.1205963

M3 - Article

C2 - 12386812

VL - 21

SP - 7497

EP - 7506

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 49

ER -