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. 2017 Oct 26;8(59):100187-100195.
doi: 10.18632/oncotarget.22124. eCollection 2017 Nov 21.

Calcitriol induces cell senescence of kidney cancer through JMJD3 mediated histone demethylation

Yongqing Shen  1 , Dan Yu  2 , Pan Qi  3 , Xuliang Wang  4 , Xiaoqiang Guo  5   6 , Aili Zhang  3
Affiliations

Calcitriol induces cell senescence of kidney cancer through JMJD3 mediated histone demethylation

Yongqing Shen et al. Oncotarget. .

Abstract

Calcitriol, also known as 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3), is a biologically active form of vitamin D and has a wide range of anticancer activity against various cancer cell lines. However, the mechanism of calcitriol remains to be further studied. In this study, the biological effect and epigenetic regulation of calcitriol on kidney cancer cells were investigated. Calcitriol can significantly inhibit cell proliferation of kidney cancer cell lines 786-O (P<0.05). Calcitriol also induced cell apoptosis and senescence of 786-O and ACHN (P<0.05). Calcitriol can increase the expression of histone demethylase JMJD3 and cell senescence marker p16INK4A (P<0.05). Knockdown of JMJD3 decreased p16INK4A upregulation after calcitriol treatment (P<0.05), and also reduced calcitriol-induced cell senescence (P<0.05). This study reveals a new mechanism of anticancer activity of calcitriol by showing that histone demethylase JMJD3 induced by calcitriol increases p16INK4A expression and cell senescence. Therefore, these results provide new strategy for treatment and prevention of kidney cancer.

Keywords: JMJD3; calcitriol; cell senescence; kidney cancer; p16INK4A.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no competing financial interests exist.

Figures

Figure 1
Figure 1. Calcitriol inhibits cell proliferation of kidney cancer cells
786-O (A) and HEK293 (B) cells were treated with vehicle (Veh) or 100nM calcitriol (Cal) for 24h, 48h and 72h, and untreated group as control (Con). The effects on cell proliferation were determined with MTT assay. *, P < 0.05.
Figure 2
Figure 2. Calcitriol promotes the apoptosis of kidney cancer cells
786-O and ACHN cells were treated with vehicle (Veh) or 100nM calcitriol (Cal) for 48h, and untreated group as control (Con). The cell apoptosis rates were determined by flow cytometry analysis. (A) 786-O. (B) Quantitative results of 786-O cell apoptosis. (C) ACHN. (D) Quantitative results of ACHN cell apoptosis. Scale bar, 100μm. Magnification, 200×. *, P < 0.05.
Figure 3
Figure 3. Calcitriol induces cell senescence of kidney cancer cells
786-O and ACHN cells were treated with vehicle (Veh) or 100nM calcitriol (Cal) for 48h, and untreated group as control (Con). The cell senescence was determined by SA-β-gal staining. (A) 786-O. (B) Quantitative results of 786-O cell senescence. (C) ACHN. (D) Quantitative results of cell senescence. *, P < 0.05.
Figure 4
Figure 4. Calcitriol increases the expressions of JMJD3 and p16INK4A
786-O cells were treated with vehicle (Veh) or 100nM calcitriol (Cal) for 48h, and untreated group as control (Con). The expressions of JMJD3 and p16INK4A were determined with qRT-PCR or western blotting. (A) The results of qRT-PCR. (B) The results of western blotting. *, P < 0.05.
Figure 5
Figure 5. Knockdown of JMJD3 inhibits calcitriol-induced p16INK4A upregulation and cell senescence
(A) 786-O cells were transfected with JMJD siRNA or control (Ctl) siRNA, and the knockdown effects were determined with qRT-PCR (up) and western blotting (down). (B) 786-O cells transfected with Ctl siRNA or JMJD3 siRNA were treated with vehicle (Veh) or 100nM calcitriol (Cal) for 48h, and cell senescence was determined by SA-β-gal staining. (C) Quantitative results of cell senescence. (D) The expression of p16INK4A in 786-O cells first transfected with Ctl siRNA or JMJD3 siRNA, and then treated with Veh or 100nM Cal for 48h. Scale bar, 100μm. Magnification, 200×. *, P < 0.05.
Figure 6
Figure 6. The proposed model of JMJD3 action
JMJD3 promotes cancer development by participating in promoting factor signaling pathways. JMJD3 also can inhibit tumor formation by participating in inhibitory factor signaling pathways. The transformation from normal cells to cancer cells can be realized when the activity of the promoting factor is over the inhibitory factor.
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References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2015;67:7–31. - PubMed
    1. Bhatt JR, Finelli A. Landmarks in the diagnosis and treatment of renal cell carcinoma. Nat Rev Urol. 2014;11:517–525. - PubMed
    1. Owens B. Kidney cancer. Nature. 2016;537:S97. - PubMed
    1. Mohammed A, Shergill I, Little B. Management of metastatic renal cell carcinoma: current trends. Expert Rev Mol Diagn. 2009;9:75–83. - PubMed
    1. Su D, Stamatakis L, Singer EA, Srinivasan R. Renal cell carcinoma: molecular biology and targeted therapy. Curr Opin Oncol. 2014;26:321–327. - PMC - PubMed

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