Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.

有丝分裂期间染色体的不适当分布可能导致恶性转化。高等真核生物已经进化出一种有丝分裂灾难机制来消除有丝分裂无能的细胞；然而，人们对信号级联及其表观遗传调控知之甚少。我们对人类癌组织的分析表明，NAD 依赖性脱乙酰酶 SIRT2 在各种器官的早期癌中上调。质谱分析表明，SIRT2 与染色体蛋白 1 (SMC1A) 的结构维持相互作用并使其去乙酰化，然后促进 SMC1A 磷酸化以正确驱动有丝分裂。我们进一步证明，抑制 SIRT2 活性或不断增加 SMC1A-K579 乙酰化会导致异常的染色体分离，进而，在癌细胞中诱导有丝分裂灾难并增强它们对化学治疗剂的脆弱性。这些发现表明，通过去乙酰化 - 磷酸化调节 SIRT2-SMC1A 轴可以避免有丝分裂灾难，从而使早期前体病变能够克服致癌压力。