RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Calcitriol/farmacología , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Glioma/tratamiento farmacológico , Histona Demetilasas con Dominio de Jumonji/metabolismo , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Metilación de ADN/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioma/enzimología , Glioma/genética , Glioma/patología , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Regiones Promotoras Genéticas , Transducción de SeñalRESUMEN
Purpose To investigate the role of ICA II in subarachnoid hemorrhage (SAH)- related chronic hydrocephalus. Methods A two hemorrhage injection model of SAH was created in Sprague Dawley rats (6-8 weeks). A total of 125 rats were randomly assigned into five groups: Sham group, SAH group, SAH+ ICA II (1 mg/kg) group, SAH + ICA II (5 mg/kg) group, and SAH + ICA II (10 mg/kg) group. TGF-ß1, phospho-Smad2/3, connective tissue growth factor (CTGF), and procollagen type I carboxy-terminal propeptide (PICP) were assessed via real-time PCR, Western blotting, and enzyme-linked immunosorbent assay. Lateral ventricular index, Masson staining, and Morris water maze tests were employed to evaluate subarachnoid fibrosis, hydrocephalus, and long term neurological function following SAH. Results ICA II (1, 5, 10 mg/kg) inhibited subarachnoid fibrosis, attenuated ventriculomegaly, and effectively suppressed SAH related chronic hydrocephalus. In addition, parallel reduced expression of members of the TGF-ß1/Smad/CTGF signaling pathway were observed. Importantly, ICA II may improve long term neurocognitive deficits after SAH. Conclusion ICA II might suppress fibrosis via inhibition of TGF-ß1/Smad/CTGF pathway, prevent the development of SAH related chronic hydrocephalus, and improve long term neurocognitive defects following SAH.