Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression: a novel regulatory network with broader significance

Abstract

In the human prostate, expression of prostate-specific genes is known to be directly regulated by the androgen–induced stimulation of the androgen receptor (AR). However, less is known about the expression control of the prostate-restricted TGM4 (hTGP) gene. In the present study we demonstrate that the regulation of the hTGP gene depends mainly on retinoic acid (RA). We provide evidence that the retinoic acid receptor gamma (RAR-G) plays a major role in the regulation of the hTGP gene and that presence of the AR, but not its transcriptional transactivation activity, is critical for hTGP transcription. RA and androgen responsive elements (RARE and ARE) were mapped to the hTGP promoter by chromatin immunoprecipitation (ChIP), which also indicated that the active ARE and RARE sites were adjacent, suggesting that the antagonistic effect of androgen and RA is related to the relative position of binding sites. Publicly available AR and RAR ChIP-seq data was used to find gene potentially regulated by AR and RAR. Four of these genes (CDCA7L, CDK6, BTG1 and SAMD3) were tested for RAR and AR binding and two of them (CDCA7L and CDK6) proved to be antagonistically regulated by androgens and RA confirming that this regulation is not particular of hTGP.

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

“…These aggregate data suggest that LEDGF/p75 may regulate JPO2 via transcriptional as well as posttranscriptional mechanisms in a cell context-dependent manner. In addition to direct transcriptional functions, both LEDGF/p75 and JPO2 (42,43) have been implicated in chromatin remodelling (44)(45)(46), thus JPO2:LEDGF/p75 transcriptional complexes may have more potent, global gene regulatory roles with impact on additional as yet undefined transforming pathways in medulloblastoma. Interestingly, recent studies also suggest potential E3 ubiquitin ligase functions for JPO2 (44,47), thus JPO2 may also regulate signaling via posttranslational mechanisms.…”

The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover

“…Massie et al (37) found KDM4B to be upregulated in response to androgens after 5 h, but found no change before this. On analysis of their data by Rivera-Gonzalez et al (38), six androgen response elements were identified close to the KDM4B gene. Guseva et al (39) also identified KDM4B as an AR-regulated gene by ChIP-Seq in LNCaP cells.…”

Interactive effects of 9-cis-retinoic acid and androgen on proliferation, differentiation, and apoptosis of LNCaP prostate cancer cells

“…PSA secretion is regulated by activation of the AR, which interacts with both RARs and RXRs, forming dimers and modulating gene transcription (Rivera-Gonzalez et al, 2012), and the presence of 9cRA can alter the expression of AR target genes (Chuang et al, 2005a). Increased PSA secretion is also consistent with the observed reduction in proliferation, suggesting that cells entered a state of growth arrest, accompanied by an increased production of PSA, as expression of cellular differentiation increased.…”