Regulation of Gene Expression by 1α,25-Dihydroxyvitamin D<sub>3</sub>and Its Analog EB1089 under Growth-Inhibitory Conditions in Squamous Carcinoma Cells

Akutsu, Naotake; Lin, Roberto; Bastien, Yolande; Bestawros, Alain; Enepekides, Danny; Black, Martin J.; White, John H.

doi:10.1210/mend.15.7.0655

Cited by 45 publications

(31 citation statements)

References 45 publications

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“…This shows that GADD45 induction by 1,25VD does not require new protein synthesis, thus identifying GADD45 as a primary target gene for 1,25VD in OCa cells. This is consistent with similar data in squamous cell carcinoma (44,45).…”

Section: 25vd Suppresses Oca Cell Growth and Induces Cell Cyclesupporting

confidence: 94%

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G2/M Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through the Induction of GADD45 via an Exonic Enhancer

Jiang

Fornace

et al. 2003

Journal of Biological Chemistry

120

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Vitamin D 3 (VD) 1 is a lipophilic hormone essential for normal bone structure and maintenance of serum calcium (1). VD action is mediated through the vitamin D receptor (VDR) (2), a member of the steroid/thyroid receptor superfamily of ligandregulated transcription factors (3-5). This superfamily includes receptors for steroids such as progesterone, androgens, estrogens, glucocorticoids, and mineralocorticoids; receptors for non-steroid hormones like vitamin D, thyroid hormones, alltrans-retinoic acid and 9-cis-retinoic acid; and orphan receptors for which the ligand is unknown. VDR and other non-steroid receptor members of the superfamily form heterodimers with the retinoid X receptor (RXR), the receptor for 9-cis-retinoic acid. In most cases, the VDR⅐RXR heterodimer binds VD response elements (VDREs) to mediate the biological activities of VD through transcriptional activation or repression of target genes containing VDREs in their regulatory sequence. In response to VD activation, the VDR recruits multiple coactivators, including members of the p160 steroid receptor coactivator family (6), which are associated with histone acetyltransferase activity, and the vitamin D receptor interacting proteins complex (7); the latter serves as a mediator between the VDR and RNA polymerase II (Pol II) complex.In addition to its well defined role in calcium homeostasis and bone cell metabolism, the active metabolite of VD, 1,25-dihydroxyvitamin D 3 (1,25VD), modulates cellular proliferation and differentiation of both normal and malignant cells (8). 1,25VD and its synthetic analogues can inhibit carcinogenesis in mouse skin (9, 10), decrease the size of transplanted sarcomas, reduce lung metastasis in mice (11), suppress the growth of human colonic cancer cell-derived xenografts in immunesuppressed mice (12), and increase cell differentiation and decrease proliferation of leukemia (13), breast cancer (14), and prostate cancer (15) cells. Studies in cancer cell lines have shown that 1,25VD causes cancer cells to accumulate in the G 1 phase of the cell cycle (15) or in the G 2 phase (16) or to undergo apoptosis (17,18). Genes that mediate each of these specific activities remain largely unidentified.Similar to breast and prostate cancers, ovarian cancer (OCa) mortality and incident rates are lower in countries within 20°o f the equator (19) where there is a high amount of sunlight. In the United States, women between the ages of 45 and 54 living in the north have 5 times the OCa mortality rate than women living in southern states (20,21). In the epidermis, sunlight controls the first step of 1,25VD synthesis, namely the photoconversion of 7-dehydrocholesterol to pre-vitamin D 3 . Exposure to sunlight, rather than food consumption, is the primary source of 1,25VD (22). The inverse correlation between sunlight exposure and OCa mortality indicates that decreased synthesis of 1,25VD may contribute to OCa initiation and/or progression. VDR has been found in rat ovaries by immunohistochemistry (23) and in hen ovaries by ligand bin...

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Section: 25vd Suppresses Oca Cell Growth and Induces Cell Cyclesupporting

confidence: 94%

“…Previous studies (45) have shown that the induction of GADD45 expression in squamous cell carcinoma by VD is associated with an increased interaction with proliferating cell nuclear antigen. Although we have not examined the association of GADD45 with proliferating cell nuclear antigen, it appears unlikely to be the case in OVCAR3 cells.…”

Section: Discussionmentioning

confidence: 86%

G2/M Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through the Induction of GADD45 via an Exonic Enhancer

Jiang

Fornace

et al. 2003

Journal of Biological Chemistry

120

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“…For example, p38/MAPK-APK2 activation regulates 1a25(OH) 2 D 3 -induced HL-60 myeloid differentiation (Wang et al, 2000) and upregulation of GADD45a is a functional part of the antiproliferative action of EB1089 (an analogue of 1a,25(OH) 2 D 3 ) in SCC25 squamous carcinoma cells (Akutsu et al, 2001) and 1a,25(OH) 2 D 3 in ovarian cancer cell lines (Jiang et al, 2003a). These studies and our own re-expression data highlight these targets as key in mediating the antiproliferative action of 1a,25(OH) 2 D 3 .…”

Section: Discussionmentioning

confidence: 99%

“…These genes included those that have roles in controlling apoptosis and proliferation (GADD45a (Jin et al, 2001) (Table 2). From our preliminary validation studies, we chose to focus on MAPK-APK2 and GADD45a as these have been shown to be gene targets for NR action (Wang et al, 2000;Akutsu et al, 2001;Alsayed et al, 2001). Real-time reverse transcription-polymerase chain reaction (RT-PCR) over a 12 h time course in PC-3 cells confirmed that MAPK-APK2 mRNA was readily detected in control cells, reflecting the relatively strong control signal on the cDNA microarray, and was significantly higher than GADD45a mRNA levels (11.4-fold greater, P<0.001).…”

Section: Identification and Regulation Of Genes In Pc-3 Cells Cotreatmentioning

confidence: 99%

Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells

et al. 2004

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We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1a,25-dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (Po0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1a,25(OH) 2 D 3 can be 'restored' by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 nM) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1a,25(OH) 2 D 3 plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1a,25(OH) 2 D 3 plus TSA cooperatively upregulated eight (outof1176)genes,includingMAPK-APK2andGADD45a. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45a induction by 1a,25(OH) 2 D 3 alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45a was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1a,25(OH) 2 D 3 -insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors.

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“…Epidemiological and experimental data in cultured cells and in animal models indicate their beneficial effect against colon cancer through the inhibition of cell proliferation and invasion and the induction of pro-apoptotic and pro-differentiation activities (5-7). Global transcriptomic studies have led to the identification of a few 1α,25(OH) 2 D 3 target genes, including some that encode cell-cycle regulators (p21 WAF1/CIP1 , p27 KIP1 , several cyclins), the gene that encodes the crucial intercellular adhesion and invasion suppressor E-cadherin, and several that encode cytoskeletal proteins (8)(9)(10)(11). In addition, 1α,25(OH) 2 D 3 exerts an indirect gene-regulatory effect through the antagonism of the Wnt/β-catenin signaling pathway, which is aberrantly activated in most human colon cancers.…”

Section: Introductionmentioning

confidence: 99%

Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells

ρlvarez-Díaz

Valle²,

García³

et al. 2009

J. Clin. Invest.

101

100

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IntroductionThere is an increasing interest in the active vitamin D metabolite 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] and its analogs as preventive and therapeutic anticancer agents, and a number of clinical trials are presently underway (1-4). Epidemiological and experimental data in cultured cells and in animal models indicate their beneficial effect against colon cancer through the inhibition of cell proliferation and invasion and the induction of pro-apoptotic and pro-differentiation activities (5-7). Global transcriptomic studies have led to the identification of a few 1α,25(OH) 2 D 3 target genes, including some that encode cell-cycle regulators (p21 WAF1/CIP1 , p27 KIP1 , several cyclins), the gene that encodes the crucial intercellular adhesion and invasion suppressor E-cadherin, and several that encode cytoskeletal proteins (8-11). In addition, 1α,25(OH) 2 D 3 exerts an indirect gene-regulatory effect through the antagonism of the Wnt/β-catenin signaling pathway, which is aberrantly activated in most human colon cancers. By inducing a rapid interaction of its receptor (vitamin D receptor [VDR]) and β-catenin and the subsequent nuclear export of β-catenin, 1α,25(OH) 2 D 3 opposes the regulation of β-catenin/TCF complexes over a large number of genes in colon carcinoma cells (12,13).

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Regulation of Gene Expression by 1α,25-Dihydroxyvitamin D₃and Its Analog EB1089 under Growth-Inhibitory Conditions in Squamous Carcinoma Cells

Cited by 45 publications

References 45 publications

G2/M Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through the Induction of GADD45 via an Exonic Enhancer

G2/M Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through the Induction of GADD45 via an Exonic Enhancer

Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells

Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells

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Regulation of Gene Expression by 1α,25-Dihydroxyvitamin D3and Its Analog EB1089 under Growth-Inhibitory Conditions in Squamous Carcinoma Cells

Cited by 45 publications

References 45 publications

G2/M Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through the Induction of GADD45 via an Exonic Enhancer

G2/M Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through the Induction of GADD45 via an Exonic Enhancer

Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells

Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells

Contact Info

Product

Resources

About

Regulation of Gene Expression by 1α,25-Dihydroxyvitamin D₃and Its Analog EB1089 under Growth-Inhibitory Conditions in Squamous Carcinoma Cells