Cholesterol sulfonation enzyme, SULT2B1b, modulates AR and cell growth properties in prostate cancer

Renee E. Vickman, Scott A. Crist, Kevin Kerian, Livia Eberlin, R. Graham Cooks, Grant N. Burcham, Kimberly K. Buhman, Chang Deng Hu, Andrew D. Mesecar, Liang Cheng, Timothy L. Ratliff

Research output: Contribution to journalArticle

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Abstract

Cholesterol accumulates in prostate lesions and has been linked to prostate cancer incidence and progression. However, how accumulated cholesterol contributes to prostate cancer development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared with normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides a growth advantage to these cells. To address this, prostate cancer cells with RNAi-mediated knockdown (KD) of SULT2B1b were used to assess the impact on cell growth and survival. SULT2B1b is expressed and functional in a variety of prostate cells, and the data demonstrate that SULT2B1b KD, in LNCaP and other androgen-responsive (VCaP and C4-2) cells, results in decreased cell growth/viability and induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression has no impact on SULT2B1b KD-mediated cell death, the addition of exogenous androgen is able to partially rescue the growth inhibition induced by SULT2B1b KD in LNCaP cells. These results suggest that SULT2B1b positively regulates the AR either through alterations in ligand availability or by interaction with critical coregulators that influence AR activity. Implications: These findings provide evidence that SULT2B1b is a novel regulator of AR activity and cell growth in prostate cancer and should be further investigated for therapeutic potential.

Original languageEnglish (US)
Pages (from-to)776-786
Number of pages11
JournalMolecular Cancer Research
Volume14
Issue number9
DOIs
StatePublished - Sep 1 2016

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Androgen Receptors
Prostatic Neoplasms
Cholesterol
Enzymes
Growth
Prostate
Androgens
Cell Survival
Cell Death
Prostatic Intraepithelial Neoplasia
RNA Interference
Adenocarcinoma
Ligands
Messenger RNA
Incidence
cholesteryl sulfate
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Vickman, R. E., Crist, S. A., Kerian, K., Eberlin, L., Graham Cooks, R., Burcham, G. N., ... Ratliff, T. L. (2016). Cholesterol sulfonation enzyme, SULT2B1b, modulates AR and cell growth properties in prostate cancer. Molecular Cancer Research, 14(9), 776-786. https://doi.org/10.1158/1541-7786.MCR-16-0137

Cholesterol sulfonation enzyme, SULT2B1b, modulates AR and cell growth properties in prostate cancer. / Vickman, Renee E.; Crist, Scott A.; Kerian, Kevin; Eberlin, Livia; Graham Cooks, R.; Burcham, Grant N.; Buhman, Kimberly K.; Hu, Chang Deng; Mesecar, Andrew D.; Cheng, Liang; Ratliff, Timothy L.

In: Molecular Cancer Research, Vol. 14, No. 9, 01.09.2016, p. 776-786.

Research output: Contribution to journalArticle

Vickman, RE, Crist, SA, Kerian, K, Eberlin, L, Graham Cooks, R, Burcham, GN, Buhman, KK, Hu, CD, Mesecar, AD, Cheng, L & Ratliff, TL 2016, 'Cholesterol sulfonation enzyme, SULT2B1b, modulates AR and cell growth properties in prostate cancer', Molecular Cancer Research, vol. 14, no. 9, pp. 776-786. https://doi.org/10.1158/1541-7786.MCR-16-0137
Vickman, Renee E. ; Crist, Scott A. ; Kerian, Kevin ; Eberlin, Livia ; Graham Cooks, R. ; Burcham, Grant N. ; Buhman, Kimberly K. ; Hu, Chang Deng ; Mesecar, Andrew D. ; Cheng, Liang ; Ratliff, Timothy L. / Cholesterol sulfonation enzyme, SULT2B1b, modulates AR and cell growth properties in prostate cancer. In: Molecular Cancer Research. 2016 ; Vol. 14, No. 9. pp. 776-786.
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abstract = "Cholesterol accumulates in prostate lesions and has been linked to prostate cancer incidence and progression. However, how accumulated cholesterol contributes to prostate cancer development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared with normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides a growth advantage to these cells. To address this, prostate cancer cells with RNAi-mediated knockdown (KD) of SULT2B1b were used to assess the impact on cell growth and survival. SULT2B1b is expressed and functional in a variety of prostate cells, and the data demonstrate that SULT2B1b KD, in LNCaP and other androgen-responsive (VCaP and C4-2) cells, results in decreased cell growth/viability and induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression has no impact on SULT2B1b KD-mediated cell death, the addition of exogenous androgen is able to partially rescue the growth inhibition induced by SULT2B1b KD in LNCaP cells. These results suggest that SULT2B1b positively regulates the AR either through alterations in ligand availability or by interaction with critical coregulators that influence AR activity. Implications: These findings provide evidence that SULT2B1b is a novel regulator of AR activity and cell growth in prostate cancer and should be further investigated for therapeutic potential.",
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AU - Graham Cooks, R.

AU - Burcham, Grant N.

AU - Buhman, Kimberly K.

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AU - Mesecar, Andrew D.

AU - Cheng, Liang

AU - Ratliff, Timothy L.

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AB - Cholesterol accumulates in prostate lesions and has been linked to prostate cancer incidence and progression. However, how accumulated cholesterol contributes to prostate cancer development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared with normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides a growth advantage to these cells. To address this, prostate cancer cells with RNAi-mediated knockdown (KD) of SULT2B1b were used to assess the impact on cell growth and survival. SULT2B1b is expressed and functional in a variety of prostate cells, and the data demonstrate that SULT2B1b KD, in LNCaP and other androgen-responsive (VCaP and C4-2) cells, results in decreased cell growth/viability and induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression has no impact on SULT2B1b KD-mediated cell death, the addition of exogenous androgen is able to partially rescue the growth inhibition induced by SULT2B1b KD in LNCaP cells. These results suggest that SULT2B1b positively regulates the AR either through alterations in ligand availability or by interaction with critical coregulators that influence AR activity. Implications: These findings provide evidence that SULT2B1b is a novel regulator of AR activity and cell growth in prostate cancer and should be further investigated for therapeutic potential.

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