甲状腺癌复发转移是临床诊治的难点，单纯的遗传学改变尚不能解释其转移机制。表观修饰异常与肿瘤转移密切相关，其作用依赖于不同表观调控元件的组装。我们发表于Oncogene的研究已证实MKL1可促进甲基转移酶复合物组装，是重要的表观遗传调节因子。进一步研究发现MKL1在甲状腺乳头状癌中的高表达与肿瘤的远端及淋巴结转移密切相关；MKL1协同染色质重塑蛋白BRG1激活MMP2的表达。而BRG1可结合组蛋白修饰酶组成复合物调控靶基因转录活性，因此，我们提出“MKL1介导BRG1-组蛋白修饰酶(COMPASS)复合物组装以促进MMP2表达”的假说。本项目拟通过“临床-细胞-动物”层次证实MKL1促进甲状腺癌的侵袭转移；使用报告基因、IP和ChIP等手段解析由MKL1招募的表观调控元件的组装及其对下游靶基因MMP2的转录激活，揭示表观遗传复合物组装促进甲癌侵袭转移的分子机理，为甲癌治疗提供新的干预靶标。

The metastasis with recurrence is always the most concerning issue for thyroid cancer diagnosis and treatment. Therefore, probing the mechanism of thyroid cancer metastasis and uncovering the key molecular marker are important for building more effective diagnosis and treatment methods. Increasing evidences showed that MKL1 acted as a transcription regulator which participate in multiple physiological process and pathogenesis. We found that MKL1 is overexpressed in thyroid cancer and significantly corelated with extracapsular spread and lymph node metastasis. Furthermore, we found that the overexpression of MKL1 and BRG1 can upregulate the transcription of MMP2 promoter. Taken all these results together, we hypothesized that “MKL1 mediated the transcription of MMP2 through the recruitment of BRG1 and other histone modifier”. In our study, we will confirm the corelation of MKL1 with distant metastasis and lymph node metastasis in papillary thyroid sample as well as in cell and mice model. And we will investigate the mechanism of MKL1 and BRG1 in MMP2 transcription in vitro and in vivo. We hope our study will help to unvil a new epigenetic mechanism accounting for thyroid cancer metastasis and providing a new druggable target for thyroid cancer metastasis.