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

doi: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

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^*

^*Corresponding author for this work

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

33 Citations (Scopus)

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.

Original language	English
Pages (from-to)	82-90
Number of pages	9
Journal	Cancer Letters
Volume	277
Issue number	1
DOIs	https://doi.org/10.1016/j.canlet.2008.11.030
Publication status	Published - 8 May 2009
Externally published	Yes

Keywords

EBBP
TRIM protein
RARβ
HDAC inhibitor
retinoid

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10.1016/j.canlet.2008.11.030

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Raif, A., Marshall, G. M., Bell, J. L., Koach, J., Tan, O., D'andreti, C., Thomas, W., Sekyere, E., Norris, M., Haber, M., Kavallaris, M., & Cheung, B. B. (2009). The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation. Cancer Letters, 277(1), 82-90. https://doi.org/10.1016/j.canlet.2008.11.030

@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.}",

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doi = "10.1016/j.canlet.2008.11.030",

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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

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

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U2 - 10.1016/j.canlet.2008.11.030

DO - 10.1016/j.canlet.2008.11.030

M3 - Article

C2 - 19147277

AN - SCOPUS:61849097812

SN - 0304-3835

VL - 277

SP - 82

EP - 90

JO - Cancer Letters

JF - Cancer Letters

IS - 1

ER -

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

Abstract

Keywords

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