Gupta Piyushi, Sheikh Touseef, Sen Ellora
National Brain Research Centre, Manesar, Haryana 122051, India.
National Brain Research Centre, Manesar, Haryana 122051, India.
Exp Cell Res. 2017 Aug 1;357(1):98-106. doi: 10.1016/j.yexcr.2017.05.005. Epub 2017 May 4.
To understand the molecular association between inflammation and dysregulated metabolism in glioblastoma, the effect of IL-1β on Hexokinase 2 (HK2) expression was investigated. IL-1β induced HK2 expression was accompanied by heightened SIRT6 and MZF1 levels. IL-1β mediated overall decrease in chromatin compactness on HK2 promoter involved diminished nucleosomal occupancy around the most labile region bearing MZF1 sites. Importantly, SIRT6 and MZF1 served as negative regulators of HK2. Ectopic SIRT6 induced formation and recruitment of MZF1-SIRT6 complex to MZF1 site was concomitant with increased nucleosomal occupancy. The function of SIRT6 as co-repressor of MZF1 was inconspicuous in cells treated with IL-1β alone, as IL-1β-induced HIF-1α prevented SIRT6 availability for interaction with MZF1. Taken together, SIRT6 over-expression establishes a condition whereby reconfiguration of the HK2 promoter chromatin structure makes it receptive to interaction with MZF1/SIRT6 complex, thereby favouring a regulatory state conducive to diminished transcription.
为了解胶质母细胞瘤中炎症与代谢失调之间的分子关联，研究了白细胞介素-1β（IL-1β）对己糖激酶2（HK2）表达的影响。IL-1β诱导的HK2表达伴随着沉默调节蛋白6（SIRT6）和髓锌指蛋白1（MZF1）水平的升高。IL-1β介导的HK2启动子染色质紧致度总体下降涉及在含有MZF1位点的最不稳定区域周围核小体占有率降低。重要的是，SIRT6和MZF1作为HK2的负调节因子。异位表达的SIRT6诱导MZF1-SIRT6复合物形成并募集至MZF1位点，同时核小体占有率增加。在单独用IL-1β处理的细胞中，SIRT6作为MZF1的共抑制因子的功能不明显，因为IL-1β诱导的缺氧诱导因子-1α（HIF-1α）阻止了SIRT6与MZF1相互作用。综上所述，SIRT6过表达建立了一种条件，即HK2启动子染色质结构的重新配置使其易于与MZF1/SIRT6复合物相互作用，从而有利于转录减少的调节状态。
