SIRT7 Facilitates CENP-A Nucleosome Assembly and Suppresses Intestinal Tumorigenesis
SIRT7 Facilitates CENP-A Nucleosome Assembly and Suppresses Intestinal Tumorigenesis
复制标题
SIRT7 促进 CENP-A 核小体组装并抑制肠道肿瘤发生
DOI：
10.1016/j.isci.2020.101461
复制
发表时间：
2020-09-25
期刊：
影响因子：
5.8
通讯作者：
Tang, Yun-Chi
中科院分区：
文献类型：
--
作者：
Liu, Xiyang;Li, Chengling;Tang, Yun-Chi
SIRT7 是哺乳动物去乙酰化酶的成员，具有 NAD(+) 依赖性脱酰酶的功能。在这里，我们发现 SIRT7 缺陷会导致组蛋白乙酰转移酶 1 (HAT1) 活性降低，从而降低组蛋白 H4K5 和 H4K12 乙酰化。这反过来会导致着丝粒处的 CENP-A 错位，从而进一步影响染色质组装。 SIRT7 消融会导致非整倍体和衰老表型，包括衰老和核仁扩张。此外，SIRT7 敲除小鼠容易受到 DSS 诱导的结肠炎和酒精源性上皮紊乱的影响，这表明肠上皮稳态被破坏。值得注意的是，SIRT7 的缺失会加剧 APC(Min/+) 小鼠模型中结直肠癌发病的易感性，并进一步引发 Wnt 信号传导。我们的研究结果表明 SIRT7 在结直肠癌中具有肿瘤抑制作用。与维持基因组完整性和肠道稳态的活动一起，激活 SIRT7 可能作为治疗肠道疾病和结直肠癌的策略。
SIRT7 is a member of the mammalian sirtuins and functions as an NAD(+)-dependent deacylase. Here we show that SIRT7 deficiency leads to a lowered histone acetyltransferase 1 (HAT1) activity and therefore decreased histone H4K5 and H4K12 acetylation. This in turn causes CENP-A dislocation at the centromere, which further affects chromatin assembly. SIRT7 ablation results in aneuploidy and aging phenotypes, including senescence and nucleolar expansion. Moreover, SIRT7 knockout mice are susceptible to DSS-induced colitis and alcohol-derived epithelial disturbance, revealing a disrupted intestinal epithelial homeostasis. Notably, absence of SIRT7 aggravates the susceptibility of colorectal cancer incidence in APC(Min/+) mouse model and elicits further the Wnt signaling. Our findings indicate a tumor suppressive role of SIRT7 in the case of colorectal cancer. Together with the activities in maintaining genome integrity and intestinal homeostasis, activating SIRT7 may serve as a strategy to treat bowel diseases and colorectal cancer.