Song Ha Yong, Rellinger Eric J, Park Seong-Hoon, Paul Pritha, Qiao Jingbo, Vasilopoulos Athanasios, Ozden Ozkan, Gius David, Chung Dai H
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical Center, Chicago, IL, U.S.A.
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, U.S.A.
Anticancer Res. 2018 Feb;38(2):647-654. doi: 10.21873/anticanres.12268.
BACKGROUND/AIM: Sirtuins (SIRTs) play crucial roles in various signaling pathways that modulate differentiation and proliferation. We sought to elucidate the role of SIRTs in differentiation and proliferation of human neuroblastoma (NB).
NB cells were treated with nicotinamide (NAM), a non-specific SIRT inhibitor, SIRT-targeted short hairpin RNAs, and retinoic acid to assess cell growth and differentiation.
SIRTs are involved in proliferation and differentiation using NAM in BE(2)-C cells. Specifically, SIRT6 knockdown in BE(2)-C cells reduced cell proliferation, induced neurite extension, corresponding with induction of p21 expression and G cell-cycle arrest. These effects were rescued by forced re-overexpression of SIRT6. SIRT6 expression was reduced in differentiated human NB sections, and RA-induced differentiation in BE(2)-C cells.
SIRTs have important oncogenic properties in NB beyond its established functions in aging and genome stability. SIRT6 may represent a novel target for developing future therapeutics for the treatment of aggressive NBs.
背景/目的：沉默调节蛋白（SIRTs）在调节分化和增殖的各种信号通路中发挥关键作用。我们试图阐明SIRTs在人类神经母细胞瘤（NB）分化和增殖中的作用。
用烟酰胺（NAM，一种非特异性SIRT抑制剂）、靶向SIRT的短发夹RNA和视黄酸处理NB细胞，以评估细胞生长和分化。
在BE(2)-C细胞中，利用NAM发现SIRTs参与增殖和分化。具体而言，BE(2)-C细胞中SIRT6基因敲低可减少细胞增殖、诱导神经突延伸，这与p21表达的诱导和G期细胞周期停滞相对应。通过强制重新过表达SIRT6可挽救这些效应。在分化的人类NB切片以及RA诱导的BE(2)-C细胞分化中，SIRT6表达降低。
SIRTs在NB中具有重要的致癌特性，超出了其在衰老和基因组稳定性方面已确定的功能。SIRT6可能代表了开发未来侵袭性NB治疗方法的一个新靶点。
