Histone demethylase KDM6B regulates 1,25‐dihydroxyvitamin D3‐induced senescence in glioma cells

Abstract

Vitamin D is a fat‐soluble vitamin and plays an important role in calcium absorption and bone development, whose lack can cause a variety of diseases, including cancer. Human epidemiological studies suggested that vitamin D3 deficiency might increase glioma incidence, but molecular mechanism is less understood. In this study, we show that 1,25‐dihydroxyvitamin D3 (the active form of vitamin D3) induces senescence of glioma cells and increases the expression of senescence markers, INK4A and cyclin‐dependent kinase inhibitor 1A (CDKN1A). 1,25‐Dihydroxyvitamin D3 also upregulates the expression of histone demethylase, KDM6B. Knockdown of KDM6B attenuates 1,25‐dihydroxyvitamin D3‐induced senescence and upregulation of INK4A and CDKN1A. KDM6B promotes the transcription of INK4A by eliminating the trimethylation of repressive marker H3K27me3 near its promoter. This study reveals a new regulatory mechanism involved in vitamin D3 inhibition on gliomas, which is beneficial to prevention and adjuvant therapy of glioma.

Effects of vitamin D in the nervous system: Special focus on interaction with steroid hormone signalling and a possible role in the treatment of brain cancer

“…In addition, the administration of EM1 in nude mice did not produce hypercalcaemia or other side effects. An additional mechanism for the action(s) of vitamin D in glioma cells was proposed by Sui et al, who reported that 1,25‐dihydroxyvitamin D 3 increased the expression of senescence markers INK4A and cyclin‐dependent kinase inhibitor 1A (CDKN1A) in human glioblastoma cell lines U87 and U251. These findings suggest that one of the mechanisms for the inhibition of growth by 1,25‐dihydroxyvitamin D 3 (and possibly vitamin D‐like compounds) in glioma might be the induction of senescence.…”

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases their Susceptibility to Temozolomide

“…Preclinical studies using differentiated GBM cell lines employed VitD3-loaded nanoparticles to induce cytotoxicity in rat glioma cells [23] and combined VitD3 with Temozolomide, leading to synergistic cytotoxicity via enhancement of autophagy [24]. Mechanistically it was shown that calcitriol induces senescence in conventional, FCS-grown glioma cell lines [25]. Importantly, a synthetic derivative of calcitriol, alfacalcidol, has already been tested in a small patient cohort in France as an adjuvant therapy and it was reported that from 11 patients analyzed (10 GBMs, 1 Anaplastic Astrocytoma [AA]) 3 patients showed continuous improvement and finally complete regression of the tumor (2 GBM, 1 AA) and the median survival of all patients was 21 months, with the two GBM responders still alive after 4 years of follow-up [26].…”

Impact of calcitriol and an AKT inhibitor, AT7867, on survival of rat C6 glioma cells

“…These wide effects of vitamin D are driven through its receptor VDR, which also acts as a transcription factor [5,13]. Recent clinical studies revealed the association of differential expressional patterns of vitamin D with various cancer types [16,17,19,20,[31][32][33]. Indeed, preclinical studies have shown that calcitriol or its analogues might have potential therapeutic effect as an anticancer agent [5-8, 13, 15, 34].…”

“…In contrast, the inhibitors of CDKs such as p16, p21 and p27 suppress the activation of cyclin-cyclin dependent kinase (C-CDK) complex, so the lack of activation of C-CDK results in the inhibition of cell cycle progression in the G0/G1 phase. This interaction describes the mechanism by which calcitriol prevents the proliferation of tumor cells [16][17][18].…”