Effect of retinoic acid on prostatic development

Aboseif, Sherif R.; Dahiya, Rajvir; Narayan, Perinchery; Cunha, Gerald R.

doi:10.1002/(sici)1097-0045(19970515)31:3<161::aid-pros3>3.0.co;2-o

Cited by 33 publications

(13 citation statements)

References 32 publications

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“…However, the previously reported role of androgen in hTGP regulation is reminiscent of an indirect regulation (21), since (i) no canonical AREs were found in the proximal promoter and (ii) the androgen stimulation was carried out over ten days in contrast to most direct AR stimulations, which require only 24 h treatment. The presence of putative AREs and RAREs within the extended hTGP promoter we describe here, suggested a direct role for androgen and atRA in hTGP, regulation, as both compounds play a critical role in prostate development and differentiation (13,14,46,48). However, our data indicates that atRA played the major role in the regulation of hTGP expression in both luminally-differentiated prostate cancer cell lines LNCaP and PC346C, while the benign and basal cell lines PNT1A and PNT2C2 showed little response to atRA treatment (Figure 2B).…”

Section: Discussionmentioning

confidence: 57%

“…Among the RARs, RAR-B and RAR-G seem to play a major role in prostate biology. RAR-B and RAR-G are expressed in the rat prostate at an early stage; RAR-G deficient mice show prostate malformations and RAR-B is often down-regulated in prostate cancer (17,45,46) making these genes obvious candidates to control hTGP expression. Therefore, LNCaP cells were transfected with specific siRNA targeting either RAR-B or RAR-G mRNA, to determine the specific RAR(s) responsible for atRA induced hTGP expression.…”

Section: Resultsmentioning

confidence: 99%

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

Rivera-Gonzalez

Droop

Rippon

et al. 2012

Nucleic Acids Research

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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.

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Section: Discussionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

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

Rivera-Gonzalez

Droop

Rippon

et al. 2012

Nucleic Acids Research

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“…Depending on the stage of prostate development, RA can either positively 43 or negatively affect prostate formation and gland development. 44 Given the inhibitory effects on adult stem and amplifying cells, both RARRES1 and LXN could have a role in embryonic morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN

et al. 2013

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The mouse haematopoietic stem cell (SC) regulator Latexin (LXN) is the only known homologue of the retinoic acid receptor responder 1 (RARRES1) gene. Both genes lie adjacent on chromosome 3 and differ mostly by the presence of a transmembrane domain in RARRES1. Despite their homology, it is not known whether they possess similar regulatory mechanisms, cellular localization and function. Here, we identified RARRES1 and LXN as highly significantly downregulated genes in human prostate SCs, whose expression was induced by the pro-differentiation agent all-trans retinoic acid (atRA). AtRA induced expression in the most differentiated cells compared with the SC fraction, suggesting that this subpopulation was less responsive to atRA. Small interfering RNA suppression of RARRES1 and LXN enhanced the SC properties of primary prostate cultures, as shown by a significant increase in their colony-forming ability. Expression of both RARRES1 and LXN was co-ordinately repressed by DNA methylation in prostate cancer cell lines and inhibition of RARRES1 and LXN increased the invasive capacity of primary prostate cultures, which also fully rescued an inhibitory effect induced by atRA. Moreover, we showed that RARRES1 and LXN reside within different sub-cellular compartments, providing evidence that RARRES1 is not a plasma membrane protein as previously supposed but is located primarily in the endoplasmic reticulum; whereas LXN was detected in the nucleus of prostate epithelial cells. Thus, LXN and RARRES1 are potential tumour suppressor genes, which are co-ordinately regulated, SC-silenced genes functioning to suppress invasion and colony-forming ability of prostate cancer cells; yet the proteins reside within different sub-cellular compartments.

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“…Androgens are required to maintain the secretory (differentiation-related) function of the luminal epithelial cells of normal prostate as depletion of androgens by surgical or chemical means triggers apoptosis and/or dedifferentiation of these cells [26]–[29]. Our recent studies have shown that retinoids, which also regulate the proliferation and differentiation of prostate epithelial cells [28], [30], also enhance the assembly of Cx32 into GJs [31]. These studies lend credence to the notion that formation and degradation of GJs may be linked to the proliferation and differentiation of luminal prostate epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D3 Regulates the Formation and Degradation of Gap Junctions in Androgen-Responsive Human Prostate Cancer Cells

et al. 2014

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1α-25(OH)2 vitamin D3 (1-25D), an active hormonal form of Vitamin D3, is a well-known chemopreventive and pro-differentiating agent. It has been shown to inhibit the growth of several prostate cancer cell lines. Gap junctions, formed of proteins called connexins (Cx), are ensembles of cell-cell channels, which permit the exchange of small growth regulatory molecules between adjoining cells. Cell-cell communication mediated by gap junctional channels is an important homeostatic control mechanism for regulating cell growth and differentiation. We have investigated the effect of 1-25D on the formation and degradation of gap junctions in an androgen-responsive prostate cancer cell line, LNCaP, which expresses retrovirally-introduced Cx32. Connexin32 is expressed by the luminal and well-differentiated cells of normal prostate and prostate tumors. Our results document that 1-25D enhances the expression of Cx32 and its subsequent assembly into gap junctions. Our results further show that 1-25D prevents androgen-regulated degradation of Cx32, post-translationally, independent of androgen receptor (AR)-mediated signaling. Finally, our findings document that formation of gap junctions sensitizes Cx32-expressing LNCaP cells to the growth inhibitory effects of 1-25D and alters their morphology. These findings suggest that the growth-inhibitory effects of 1-25D in LNCaP cells may be related to its ability to modulate the assembly of Cx32 into gap junctions.

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Effect of retinoic acid on prostatic development

Cited by 33 publications

References 32 publications

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

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

Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN

Vitamin D3 Regulates the Formation and Degradation of Gap Junctions in Androgen-Responsive Human Prostate Cancer Cells

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