Wang Jie, Yan Hai-Bo, Zhang Qian, Liu Wei-Yan, Jiang Ying-Hua, Peng Gang, Wu Fei-Zhen, Liu Xin, Yang Peng-Yuan, Liu Feng
Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China.
Institutes of Brain Science, Fudan University, Shanghai, China.
Oncogene. 2021 Sep;40(36):5468-5481. doi: 10.1038/s41388-021-01930-2. Epub 2021 Jul 21.
The ARID1A gene, which encodes a subunit of the SWI/SNF chromatin remodeling complex, has been found to be frequently mutated in many human cancer types. However, the function and mechanism of ARID1A in cancer metastasis are still unclear. Here, we show that knockdown of ARID1A increases the ability of breast cancer cells to proliferate, migrate, invade, and metastasize in vivo. The ARID1A-related SWI/SNF complex binds to the second exon of CDH1 and negatively modulates the expression of E-cadherin/CDH1 by recruiting the transcriptional repressor ZEB2 to the CDH1 promoter and excluding the presence of RNA polymerase II. The silencing of CDH1 attenuated the migration, invasion, and metastasis of breast cancer cells in which ARID1A was silenced. ARID1A depletion increased the intracellular enzymatic processing of E-cadherin and the production of C-terminal fragment 2 (CTF2) of E-cadherin, which stabilized β-catenin by competing for binding to the phosphorylation and degradation complex of β-catenin. The matrix metalloproteinase inhibitor GM6001 inhibited the production of CTF2. In zebrafish and nude mice, ARID1A silencing or CTF2 overexpression activated β-catenin signaling and promoted migration/invasion and metastasis of cancer cells in vivo. The inhibitors GM6001, BB94, and ICG-001 suppressed the migration and invasion of cancer cells with ARID1A-deficiency. Our findings provide novel insights into the mechanism of ARID1A metastasis and offer a scientific basis for targeted therapy of ARID1A-deficient cancer cells.
编码SWI/SNF染色质重塑复合物一个亚基的ARID1A基因，已发现在多种人类癌症类型中频繁发生突变。然而，ARID1A在癌症转移中的功能和机制仍不清楚。在此，我们表明敲低ARID1A可增强乳腺癌细胞在体内的增殖、迁移、侵袭和转移能力。与ARID1A相关的SWI/SNF复合物结合至CDH1的第二个外显子，并通过将转录抑制因子ZEB2募集至CDH1启动子并排除RNA聚合酶II的存在，对E-钙黏蛋白/CDH1的表达进行负向调节。CDH1沉默减弱了ARID1A沉默的乳腺癌细胞的迁移、侵袭和转移。ARID1A缺失增加了E-钙黏蛋白的细胞内酶促加工过程以及E-钙黏蛋白C末端片段2（CTF2）的产生，CTF2通过竞争结合β-连环蛋白的磷酸化和降解复合物而使β-连环蛋白稳定。基质金属蛋白酶抑制剂GM6001抑制CTF2的产生。在斑马鱼和裸鼠中，ARID1A沉默或CTF2过表达激活β-连环蛋白信号并促进癌细胞在体内的迁移/侵袭和转移。抑制剂GM6001、BB94和ICG-001抑制了ARID1A缺陷癌细胞的迁移和侵袭。我们的研究结果为ARID1A转移机制提供了新的见解，并为ARID1A缺陷癌细胞的靶向治疗提供了科学依据。
