File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription

TitleOrphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription
Authors
Issue Date2018
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2018, v. 37, p. 3340-3355 How to Cite?
AbstractThe metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.
Persistent Identifierhttp://hdl.handle.net/10722/263882
ISSN
2017 Impact Factor: 6.854
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorJia, SJ-
dc.contributor.authorWu, D-
dc.contributor.authorWang, Y-
dc.contributor.authorYou, W-
dc.contributor.authorWang, Z-
dc.contributor.authorXiao, L-
dc.contributor.authorCai, G-
dc.contributor.authorXu, Z-
dc.contributor.authorZou, C-
dc.contributor.authorWang, F-
dc.contributor.authorTeoh, JYC-
dc.contributor.authorNg, CF-
dc.contributor.authorYu, S-
dc.contributor.authorChan, FL-
dc.date.accessioned2018-10-22T07:45:57Z-
dc.date.available2018-10-22T07:45:57Z-
dc.date.issued2018-
dc.identifier.citationOncogene, 2018, v. 37, p. 3340-3355-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/263882-
dc.description.abstractThe metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleOrphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription-
dc.typeArticle-
dc.identifier.emailJia, SJ: jjia@hku.hk-
dc.identifier.authorityJia, SJ=rp01801-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41388-018-0198-z-
dc.identifier.hkuros294302-
dc.identifier.volume37-
dc.identifier.spage3340-
dc.identifier.epage3355-
dc.identifier.isiWOS:000436411300002-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats