Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling
Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling
复制标题
DOI：
10.1093/hmg/ddt604
复制
发表时间：
2014-04-15
影响因子：
3.5
通讯作者：
Escaffit, Fabrice
中科院分区：
文献类型：
--
作者：
Chevillard-Briet, Martine;Quaranta, Muriel;Escaffit, Fabrice
癌症进展与表观遗传改变相关，例如DNA甲基化、组蛋白修饰或变体掺入的变化。p400 ATP酶（可掺入H2A.Z变体）和Tip 60组蛋白乙酰转移酶是相互作用的染色质修饰蛋白，对于控制细胞增殖至关重要。我们在这里证明，Tip 60作为一种肿瘤抑制剂在结肠，因为小鼠Tip 60杂合子更容易受到化学诱导的癌前病变和腺瘤。引人注目的是，p400的杂合性逆转了肿瘤前病变的Tip 60依赖性形成，首次揭示了p400的促癌功能。通过全基因组分析和体内使用特异性抑制剂，我们证明了这些作用依赖于Wnt信号传导，该信号传导受到p400和Tip 60的拮抗性影响：p400直接有利于Wnt靶基因和调节子的表达，而Tip 60阻止β-连环蛋白乙酰化和活化。总之，我们的数据强调了染色质修饰酶在控制癌症相关信号通路中相互作用的生理病理学重要性。
Cancer progression is associated with epigenetic alterations, such as changes in DNA methylation, histone modifications or variants incorporation. The p400 ATPase, which can incorporate the H2A.Z variant, and the Tip60 histone acetyltransferase are interacting chromatin-modifying proteins crucial for the control of cell proliferation. We demonstrate here that Tip60 acts as a tumor suppressor in colon, since mice heterozygous for Tip60 are more susceptible to chemically induced preneoplastic lesions and adenomas. Strikingly, heterozygosity for p400 reverses the Tip60-dependent formation of preneoplastic lesions, uncovering for the first time pro-oncogenic functions for p400. By genome-wide analysis and using a specific inhibitor in vivo, we demonstrated that these effects are dependent on Wnt signaling which is antagonistically impacted by p400 and Tip60: p400 directly favors the expression of a subset of Wnt-target genes and regulators, whereas Tip60 prevents -catenin acetylation and activation. Taken together, our data underline the physiopathological importance of interplays between chromatin-modifying enzymes in the control of cancer-related signaling pathways.