Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Oncogene. 2018 Nov;37(45):5939-5951. doi: 10.1038/s41388-018-0371-4. Epub 2018 Jul 6.
As one of the primary members of SWI/SNF chromatin remodeling complexes, ARID1A contains frequent loss-of-function mutations in many types of cancers. However, the molecular mechanisms underlying ARID1A deficiency in cancer biology remain to be investigated. Using breast cancer as a model, we report that silencing ARID1A significantly increased cellular proliferation and migration. Mechanistically, primarily functioning as a transcriptional repressor, loss of ARID1A profoundly alters histone modifications and the transcriptome. Notably, ARID1A inhibited the expression of a long non-coding RNA, UCA1, by regulating chromatin access of the transcription factor CEBPα. Restoration experiments showed that UCA1 mediates the functions of ARID1A that induces loss of cellular proliferation and migration. Together, our findings characterize ARID1A as a key tumor-suppressor gene in breast cancer through cooperation with CEBPα, and loss-of-function mutations of ARID1A activates UCA1.
作为 SWI/SNF 染色质重塑复合物的主要成员之一，ARID1A 在许多类型的癌症中存在频繁的功能丧失突变。然而，ARID1A 缺陷在癌症生物学中的分子机制仍有待研究。我们以乳腺癌为模型，报告称沉默 ARID1A 可显著增加细胞增殖和迁移。从机制上讲，ARID1A 主要作为转录抑制因子发挥作用，其缺失会深刻改变组蛋白修饰和转录组。值得注意的是，ARID1A 通过调节转录因子 CEBPα 的染色质可及性来抑制长非编码 RNA UCA1 的表达。恢复实验表明，UCA1 介导 ARID1A 诱导的细胞增殖和迁移丧失的功能。总之，我们的研究结果表明，ARID1A 通过与 CEBPα 合作成为乳腺癌中的关键肿瘤抑制基因，而 ARID1A 的功能丧失突变会激活 UCA1。
