The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation

Anna Raif, Glenn M. Marshall, Jessica L. Bell, Jessica Koach, Owen Tan, Carla D'andreti, Wayne Thomas, Eric Sekyere, Murray Norris, Michelle Haber, Maria Kavallaris, Belamy B. Cheung

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) β2 is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARβ2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARβ2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARβ2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (βRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARβ2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.

LanguageEnglish
Pages82-90
Number of pages9
JournalCancer Letters
Volume277
Issue number1
DOIs
Publication statusPublished - 8 May 2009
Externally publishedYes

Fingerprint

Retinoids
Acetylation
Histones
Estrogens
Neoplasms
IgA receptor
Retinoic Acid Receptors
Histone Deacetylase Inhibitors
Cyclin D1
Response Elements
Drug Discovery
Tretinoin
Chromatin
Lung Neoplasms
Cell Survival

Keywords

  • EBBP
  • TRIM protein
  • RARβ
  • HDAC inhibitor
  • retinoid

Cite this

Raif, Anna ; Marshall, Glenn M. ; Bell, Jessica L. ; Koach, Jessica ; Tan, Owen ; D'andreti, Carla ; Thomas, Wayne ; Sekyere, Eric ; Norris, Murray ; Haber, Michelle ; Kavallaris, Maria ; Cheung, Belamy B. / The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation. In: Cancer Letters. 2009 ; Vol. 277, No. 1. pp. 82-90.
@article{bc021f3eaf0f4e339252d3ae42554e37,
title = "The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation",
abstract = "Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) β2 is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARβ2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARβ2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARβ2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (βRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARβ2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.",
keywords = "EBBP, TRIM protein, RARβ, HDAC inhibitor, retinoid",
author = "Anna Raif and Marshall, {Glenn M.} and Bell, {Jessica L.} and Jessica Koach and Owen Tan and Carla D'andreti and Wayne Thomas and Eric Sekyere and Murray Norris and Michelle Haber and Maria Kavallaris and Cheung, {Belamy B.}",
year = "2009",
month = "5",
day = "8",
doi = "10.1016/j.canlet.2008.11.030",
language = "English",
volume = "277",
pages = "82--90",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier",
number = "1",

}

Raif, A, Marshall, GM, Bell, JL, Koach, J, Tan, O, D'andreti, C, Thomas, W, Sekyere, E, Norris, M, Haber, M, Kavallaris, M & Cheung, BB 2009, 'The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation', Cancer Letters, vol. 277, no. 1, pp. 82-90. https://doi.org/10.1016/j.canlet.2008.11.030

The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation. / Raif, Anna; Marshall, Glenn M.; Bell, Jessica L.; Koach, Jessica; Tan, Owen; D'andreti, Carla; Thomas, Wayne; Sekyere, Eric; Norris, Murray; Haber, Michelle; Kavallaris, Maria; Cheung, Belamy B.

In: Cancer Letters, Vol. 277, No. 1, 08.05.2009, p. 82-90.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation

AU - Raif, Anna

AU - Marshall, Glenn M.

AU - Bell, Jessica L.

AU - Koach, Jessica

AU - Tan, Owen

AU - D'andreti, Carla

AU - Thomas, Wayne

AU - Sekyere, Eric

AU - Norris, Murray

AU - Haber, Michelle

AU - Kavallaris, Maria

AU - Cheung, Belamy B.

PY - 2009/5/8

Y1 - 2009/5/8

N2 - Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) β2 is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARβ2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARβ2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARβ2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (βRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARβ2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.

AB - Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) β2 is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARβ2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARβ2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARβ2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (βRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARβ2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.

KW - EBBP

KW - TRIM protein

KW - RARβ

KW - HDAC inhibitor

KW - retinoid

UR - http://www.scopus.com/inward/record.url?scp=61849097812&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2008.11.030

DO - 10.1016/j.canlet.2008.11.030

M3 - Article

VL - 277

SP - 82

EP - 90

JO - Cancer Letters

T2 - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 1

ER -