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

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          Abstract

          Calcitriol, also known as 1,25-dihydroxyvitamin D3 (1,25(OH) 2VD 3), 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.

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          Most cited references 36

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          Prospective study of predictors of vitamin D status and cancer incidence and mortality in men.

          Vitamin D has potent anticancer properties, especially against digestive-system cancers. Many human studies have used geographic residence as a marker of solar ultraviolet B and hence vitamin D exposure. Here, we considered multiple determinants of vitamin D exposure (dietary and supplementary vitamin D, skin pigmentation, adiposity, geographic residence, and leisure-time physical activity-to estimate sunlight exposure) in relation to cancer risk in the Health Professionals Follow-Up Study. Among 1095 men of this cohort, we quantified the relation of these six determinants to plasma 25-hydroxy-vitamin D [25(OH)D] level by use of a multiple linear regression model. We used results from the model to compute a predicted 25(OH)D level for each of 47,800 men in the cohort based on these characteristics. We then prospectively examined this variable in relation to cancer risk with multivariable Cox proportional hazards models. From 1986 through January 31, 2000, we documented 4286 incident cancers (excluding organ-confined prostate cancer and nonmelanoma skin cancer) and 2025 deaths from cancer. From multivariable models, an increment of 25 nmol/L in predicted 25(OH)D level was associated with a 17% reduction in total cancer incidence (multivariable relative risk [RR] = 0.83, 95% confidence interval [CI] = 0.74 to 0.92), a 29% reduction in total cancer mortality (RR = 0.71, 95% CI = 0.60 to 0.83), and a 45% reduction in digestive-system cancer mortality (RR = 0.55, 95% CI = 0.41 to 0.74). The absolute annual rate of total cancer was 758 per 100,000 men in the bottom decile of predicted 25(OH)D and 674 per 100,000 men for the top decile; these respective rates were 326 per 100,000 and 277 per 100,000 for total cancer mortality and 128 per 100,000 and 78 per 100,000 for digestive-system cancer mortality. Results were similar when we controlled further for body mass index or physical activity level. Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers. The vitamin D supplementation necessary to achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day.
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            Tumor cell senescence in cancer treatment.

             I B Roninson (2003)
            Cell senescence is broadly defined as the physiological program of terminal growth arrest, which can be triggered by alterations of telomeres or by different forms of stress. Neoplastic transformation involves events that inhibit the program of senescence, and tumor cells were believed until recently to have lost the ability to senesce. It has now become apparent, however, that tumor cells can be readily induced to undergo senescence by genetic manipulations or by treatment with chemotherapeutic drugs, radiation, or differentiating agents. Treatment-induced senescence, which has both similarities with, and differences from, replicative senescence of normal cells, was shown to be one of the key determinants of tumor response to therapy in vitro and in vivo. Although senescent cells do not proliferate, they remain metabolically active and produce secreted proteins with both tumor-suppressing and tumor-promoting activities. Expression of tumor-promoting factors by senescent cells is mediated, at least in part, by senescence-associated cyclin-dependent kinase inhibitors such as p21(Waf1/Cip1/Sdi1). Clinical and preclinical studies indicate that expression of different biological classes of senescence-associated growth-regulatory genes in tumor cells has significant prognostic implications. Elucidation of the genes and regulatory mechanisms that determine different aspects of tumor senescence makes it possible to design new therapeutic approaches to improving the efficacy and to decreasing the side effects of cancer therapy.
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              Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.

              The INK4a/ARF tumor suppressor locus, a key executor of cellular senescence, is regulated by members of the Polycomb group (PcG) of transcriptional repressors. Here we show that signaling from oncogenic RAS overrides PcG-mediated repression of INK4a by activating the H3K27 demethylase JMJD3 and down-regulating the methyltransferase EZH2. In human fibroblasts, JMJD3 activates INK4a, but not ARF, and causes p16(INK4a)-dependent arrest. In mouse embryo fibroblasts, Jmjd3 activates both Ink4a and Arf and elicits a p53-dependent arrest, echoing the effects of RAS in this system. Our findings directly implicate JMJD3 in the regulation of INK4a/ARF during oncogene-induced senescence and suggest that JMJD3 has the capacity to act as a tumor suppressor.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                21 November 2017
                26 October 2017
                : 8
                : 59
                : 100187-100195
                Affiliations
                1 Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050035, Hebei, China
                2 Department of Nursing, Hebei University of Chinese Medicine, Shijiazhuang 050020, Hebei, China
                3 State Engineering Laboratory of Medical Key Technologies Application of Synthetic Biology, Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, Guangdong, China
                4 Department of Urology, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, Guangdong, China
                5 Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China
                6 Longgang District Central Hospital, Shenzhen 518116, Guangdong, China
                Author notes
                Correspondence to: Aili Zhang, z13930409899@ 123456163.com
                [*]

                These authors have contributed equally to this work

                Article
                22124
                10.18632/oncotarget.22124
                5725012
                Copyright: © 2017 Shen et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Research Paper

                Oncology & Radiotherapy

                p16ink4a, kidney cancer, jmjd3, cell senescence, calcitriol

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