YY2因子在肿瘤细胞染色体不稳定性调控中的生物学机制研究

染色体不稳定性（CIN）作为肿瘤的基本特征之一，在肿瘤发生发展中具有重要作用。适当水平CIN（M-CIN）能促进肿瘤发生发展，然而过高水平的CIN（H-CIN）则能诱导肿瘤细胞死亡。YY2是阴阳因子家族的成员，与其同源因子YY1相反，YY2能抑制肿瘤细胞的增殖，但有关其生物功能的报道尚少。项目前期实验发现YY2能导致肿瘤细胞有丝分裂异常，诱发过高水平CIN的产生。然而，YY2诱发H-CIN的分子机制及其诱发H-CIN对肿瘤细胞命运调控的影响尚未清楚。本项目拟从以下三方面展开研究：(1) 阐明YY2对肿瘤细胞有丝分裂异常及H-CIN水平的作用机制；(2) 揭示YY2通过诱导H-CIN影响肿瘤细胞命运的分子调控机制；(3) 阐明YY2通过诱导H-CIN影响肿瘤发生发展以及耐药性的作用机制。本项目不仅阐明YY2诱发肿瘤细胞H-CIN产生的新生物学机制，同时也为临床肿瘤治疗干预策略提供新的思路。

Chromosomal instability (CIN) is defined as a persistently high rate of loss and gain of whole or part of chromosomes that results in the aberrant chromosome structure and number. Chromosomal instability is one of the hallmarks of tumor that plays a crucial role in tumorigenesis. Previous researches have revealed that moderate level of chromosomal instability (M-CIN) benefits tumor progression as it increases tumor heterogeneity, thus enables tumor cells to be more adaptive upon exposure to tumor microenvironment stress. Furthermore, M-CIN also increases tumor cells resistance to anti-tumor drugs. However, recent studies reported that aberrantly high CIN could induce tumor cells death. Excessive high-level CIN (H-CIN) induces genetic catastrophe, and thus eventually inhibits tumor progression.. Yin Yang 2 (YY2) is a member of Yin Yang family which originates from and shares a high homology with Yin Yang 1 (YY1). However, in contrast with YY1 which is an oncogene, recent studies showed that YY2 could suppress tumor cell proliferation. Despite its function as a tumor suppressor gene, our knowledge regarding the biological function of YY2 is still very limited. Our pilot experiments showed that YY2 overexpression suppressed the increase of colorectal carcinoma cell number as well as the expression levels of M phase regulatory proteins, indicating that YY2 overexpression inhibits cell cycle, especially M phase, progression. Furthermore, we found that YY2 overexpression elevated the number of mitotic errors, including monopolar spindle, multipolar spindle and chromosome bridge; all of which could result in chromosome structural and numeral abnormity. . We also found significant increases in the number of cells with more than 46 chromosomes, heteroploidy cells, as well as the number of micronucleus, which could increase tumor progression and metastasis, in YY2-overexpressed colorectal carcinoma cells. YY2 overexpression also promoted DNA damage. As aberrant chromosome number, heteroploidy, as well as increased micronucleus number and DNA damage are indicator of increased CIN level, these findings suggest that YY2 induces high level CIN. YY2 overexpression also induced cell death, as well as alteration of the expression of genes related to mitotic control and CIN. However, the molecular mechanism of YY2 regulation on mitosis progression and CIN, as well as its role in determining tumor cell fate remains unraveled.. In this study, we hypothesize that YY2 is involved in mitotic regulation and induction of H-CIN, and eventually plays a critical role in determining tumor cells fate as well as tumorigenesis. Thus, we aim to: (1) unravel the effect and molecular mechanism of YY2 on tumor cell mitotic error and the induction of H-CIN; (2) elucidate the regulatory mechanism of YY2-induced H-CIN on tumor cell fate, including cell proliferation and cell death; (3) reveal the effect and molecular mechanism of YY2-induced H-CIN on tumorigenesis and on suppressing tumor drug resistance. This study will not only unravel the novel molecular mechanism of YY2 regulation on tumorigenesis, but also will provide experimental evidences for the development of new combinatorial anti-tumor therapeutic strategy based on YY2 overexpression and anti-tumor drugs.