Epigenetic targeting of transforming growth factor β receptor II and implications for cancer therapy

Sanjib Chowdhury, Sudhakar Ammanamanchi, Gillian M. Howell

Research output: Contribution to journalReview article

21 Citations (Scopus)

Abstract

The transforming growth factor (TGF) β signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFβ signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFβ responsiveness frequently occurs at the level of the TGFβ type II receptor (TGFβRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFβRII expression is frequently associated with high tumor grade and poor patient prognosis. Reintroduction of TGFβRII into tumor cell lines results in growth suppression. Mutational loss of TGFβRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFβRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFβRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFβ signaling pathway. However, the restoration of TGFβ signaling in cancer treatment is challenging because in late stage disease, TGFβ is a pro-metastatic factor. This effect is associated with increased expression of the TGFβ ligand. In this Review, we discuss the mechanisms associated with TGFβRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFβRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFβ expression.

Original languageEnglish (US)
Pages (from-to)57-70
Number of pages14
JournalMolecular and Cellular Pharmacology
Volume1
Issue number1
DOIs
StatePublished - Dec 1 2009

Fingerprint

Growth Factor Receptors
Transforming Growth Factors
Epigenomics
Neoplasms
Histone Deacetylase Inhibitors
Therapeutics
Tumor Suppressor Genes
DNA Repair Enzymes
Growth
Tumor Cell Line
Colonic Neoplasms
Carcinogenesis
Apoptosis
Ligands

Keywords

  • Epigenetics
  • HDAC inhibitors
  • Histone deacetylases
  • Histone modifications
  • TGFβ RII
  • Therapy

ASJC Scopus subject areas

  • Molecular Biology
  • Pharmaceutical Science

Cite this

Epigenetic targeting of transforming growth factor β receptor II and implications for cancer therapy. / Chowdhury, Sanjib; Ammanamanchi, Sudhakar; Howell, Gillian M.

In: Molecular and Cellular Pharmacology, Vol. 1, No. 1, 01.12.2009, p. 57-70.

Research output: Contribution to journalReview article

Chowdhury, Sanjib ; Ammanamanchi, Sudhakar ; Howell, Gillian M. / Epigenetic targeting of transforming growth factor β receptor II and implications for cancer therapy. In: Molecular and Cellular Pharmacology. 2009 ; Vol. 1, No. 1. pp. 57-70.
@article{7dfc03ea391843fba64ae528f46edec3,
title = "Epigenetic targeting of transforming growth factor β receptor II and implications for cancer therapy",
abstract = "The transforming growth factor (TGF) β signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFβ signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFβ responsiveness frequently occurs at the level of the TGFβ type II receptor (TGFβRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFβRII expression is frequently associated with high tumor grade and poor patient prognosis. Reintroduction of TGFβRII into tumor cell lines results in growth suppression. Mutational loss of TGFβRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFβRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFβRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFβ signaling pathway. However, the restoration of TGFβ signaling in cancer treatment is challenging because in late stage disease, TGFβ is a pro-metastatic factor. This effect is associated with increased expression of the TGFβ ligand. In this Review, we discuss the mechanisms associated with TGFβRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFβRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFβ expression.",
keywords = "Epigenetics, HDAC inhibitors, Histone deacetylases, Histone modifications, TGFβ RII, Therapy",
author = "Sanjib Chowdhury and Sudhakar Ammanamanchi and Howell, {Gillian M.}",
year = "2009",
month = "12",
day = "1",
doi = "10.4255/mcpharmacol.09.07",
language = "English (US)",
volume = "1",
pages = "57--70",
journal = "Molecular and Cellular Pharmacology",
issn = "1938-1247",
publisher = "Lumitext Publishing",
number = "1",

}

TY - JOUR

T1 - Epigenetic targeting of transforming growth factor β receptor II and implications for cancer therapy

AU - Chowdhury, Sanjib

AU - Ammanamanchi, Sudhakar

AU - Howell, Gillian M.

PY - 2009/12/1

Y1 - 2009/12/1

N2 - The transforming growth factor (TGF) β signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFβ signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFβ responsiveness frequently occurs at the level of the TGFβ type II receptor (TGFβRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFβRII expression is frequently associated with high tumor grade and poor patient prognosis. Reintroduction of TGFβRII into tumor cell lines results in growth suppression. Mutational loss of TGFβRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFβRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFβRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFβ signaling pathway. However, the restoration of TGFβ signaling in cancer treatment is challenging because in late stage disease, TGFβ is a pro-metastatic factor. This effect is associated with increased expression of the TGFβ ligand. In this Review, we discuss the mechanisms associated with TGFβRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFβRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFβ expression.

AB - The transforming growth factor (TGF) β signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFβ signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFβ responsiveness frequently occurs at the level of the TGFβ type II receptor (TGFβRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFβRII expression is frequently associated with high tumor grade and poor patient prognosis. Reintroduction of TGFβRII into tumor cell lines results in growth suppression. Mutational loss of TGFβRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFβRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFβRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFβ signaling pathway. However, the restoration of TGFβ signaling in cancer treatment is challenging because in late stage disease, TGFβ is a pro-metastatic factor. This effect is associated with increased expression of the TGFβ ligand. In this Review, we discuss the mechanisms associated with TGFβRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFβRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFβ expression.

KW - Epigenetics

KW - HDAC inhibitors

KW - Histone deacetylases

KW - Histone modifications

KW - TGFβ RII

KW - Therapy

UR - http://www.scopus.com/inward/record.url?scp=77953406722&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953406722&partnerID=8YFLogxK

U2 - 10.4255/mcpharmacol.09.07

DO - 10.4255/mcpharmacol.09.07

M3 - Review article

C2 - 20414468

AN - SCOPUS:77953406722

VL - 1

SP - 57

EP - 70

JO - Molecular and Cellular Pharmacology

JF - Molecular and Cellular Pharmacology

SN - 1938-1247

IS - 1

ER -