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Myeloid zinc finger 1 mediates sulindac sulfide-induced upregulation of death receptor 5 of human colon cancer cells.

Horinaka M, Yoshida T, Tomosugi M, Yasuda S, Sowa Y, Sakai T - Sci Rep (2014)

Bottom Line: MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide.The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide.These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan [2].

ABSTRACT
A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of DR5 by sulindac sulfide. Sulindac sulfide induced the expression of DR5 at the protein and mRNA levels in colon cancer SW480 cells. Furthermore, sulindac sulfide increased DR5 promoter activity. We showed that sulindac sulfide stimulated DR5 promoter activity via the -301 to -253 region. This region contained a putative MZF1-binding site. Site-directed mutations in the site abrogated the enhancement in DR5 promoter activity by sulindac sulfide. MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide. The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide. These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.

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The scheme of mechanisms enhancing DR5 expression by sulindac sulfide.Sulindac sulfide increases MZF1. The transcription factor MZF1 then upregulates DR5 promoter activity through its binding site.
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f7: The scheme of mechanisms enhancing DR5 expression by sulindac sulfide.Sulindac sulfide increases MZF1. The transcription factor MZF1 then upregulates DR5 promoter activity through its binding site.

Mentions: Sulindac sulfide was previously suggested to be a candidate for a TRAIL sensitizer due to the upregulation of DR527. However, the mechanism underlying how sulindac sulfide up-regulates DR5 has not yet been elucidated. In the present study, we demonstrated for the first time that MZF1, a transcription factor containing the Zinc-finger domain, mediated the sulindac sulfide-induced upregulation of DR5. Sulindac sulfide increased DR5 protein and mRNA levels as well as upstream promoter activity (Fig. 2 and 3). We identified a responsive element regulated by sulindac sulfide using a series of mutant plasmids in the DR5 promoter, and the element contained a consensus sequence of the MZF1-binding site with 100% identity (Fig. 4 and 5a, b). Next, we confirmed the direct MZF1 binding to the putative MZF1-binding site of the DR5 promoter (Fig. 5c). Furthermore, we showed the expression of MZF1 was increased by sulindac sulfide (Fig. 6a). The overexpression of MZF1 increased DR5 promoter activity through the element and knockdown of MZF1 abrogated the upregulation of DR5 by sulindac sulfide (Fig. 6b, c). These results indicate that MZF1 is a transcriptional regulator of DR5 expression and a mediator for the induction of DR5 by sulindac sulfide (Fig. 7).


Myeloid zinc finger 1 mediates sulindac sulfide-induced upregulation of death receptor 5 of human colon cancer cells.

Horinaka M, Yoshida T, Tomosugi M, Yasuda S, Sowa Y, Sakai T - Sci Rep (2014)

The scheme of mechanisms enhancing DR5 expression by sulindac sulfide.Sulindac sulfide increases MZF1. The transcription factor MZF1 then upregulates DR5 promoter activity through its binding site.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126006&req=5

f7: The scheme of mechanisms enhancing DR5 expression by sulindac sulfide.Sulindac sulfide increases MZF1. The transcription factor MZF1 then upregulates DR5 promoter activity through its binding site.
Mentions: Sulindac sulfide was previously suggested to be a candidate for a TRAIL sensitizer due to the upregulation of DR527. However, the mechanism underlying how sulindac sulfide up-regulates DR5 has not yet been elucidated. In the present study, we demonstrated for the first time that MZF1, a transcription factor containing the Zinc-finger domain, mediated the sulindac sulfide-induced upregulation of DR5. Sulindac sulfide increased DR5 protein and mRNA levels as well as upstream promoter activity (Fig. 2 and 3). We identified a responsive element regulated by sulindac sulfide using a series of mutant plasmids in the DR5 promoter, and the element contained a consensus sequence of the MZF1-binding site with 100% identity (Fig. 4 and 5a, b). Next, we confirmed the direct MZF1 binding to the putative MZF1-binding site of the DR5 promoter (Fig. 5c). Furthermore, we showed the expression of MZF1 was increased by sulindac sulfide (Fig. 6a). The overexpression of MZF1 increased DR5 promoter activity through the element and knockdown of MZF1 abrogated the upregulation of DR5 by sulindac sulfide (Fig. 6b, c). These results indicate that MZF1 is a transcriptional regulator of DR5 expression and a mediator for the induction of DR5 by sulindac sulfide (Fig. 7).

Bottom Line: MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide.The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide.These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan [2].

ABSTRACT
A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of DR5 by sulindac sulfide. Sulindac sulfide induced the expression of DR5 at the protein and mRNA levels in colon cancer SW480 cells. Furthermore, sulindac sulfide increased DR5 promoter activity. We showed that sulindac sulfide stimulated DR5 promoter activity via the -301 to -253 region. This region contained a putative MZF1-binding site. Site-directed mutations in the site abrogated the enhancement in DR5 promoter activity by sulindac sulfide. MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide. The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide. These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.

Show MeSH
Related in: MedlinePlus