HMGN3 represses transcription of epithelial regulators to promote migration of cholangiocarcinoma in a SNAI2-dependent manner
HMGN3 represses transcription of epithelial regulators to promote migration of cholangiocarcinoma in a SNAI2-dependent manner
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DOI：
10.1096/fj.202200386r
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发表时间：
2022-07-01
期刊：
影响因子：
4.8
通讯作者：
Sashida, Goro
中科院分区：
文献类型：
--
作者：
Sorin, Supannika;Kubota, Sho;Sashida, Goro
高迁移率族核小体结合蛋白3（HMGN 3）是HMGN家族的成员之一，通过转录因子调节染色质的结构和转录。HMGN 3与多种癌症的发展有关;然而，其潜在机制仍不清楚。我们在此证明了HMGN 3的高表达与泰国东北部肝吸虫感染诱导的胆管癌（CCA）患者的转移相关。CCA细胞中HMGN 3的敲低显著损害了集落形成、迁移和侵袭的致癌特性。HMGN 3抑制CCA细胞中上皮调节基因的表达并阻断其细胞内极性，如CDH 1/E-cadherin和TJAP 1基因。染色质免疫沉淀测序分析显示，HMGN 3需要转录因子SNAI 2结合并抑制上皮调节基因的表达，至少部分是由于组蛋白脱乙酰酶（HDAC），其药理学抑制在CCA中重新激活这些上皮调节因子，导致损害细胞迁移能力。因此，HMGN 3的过表达以依赖于SNAI 2基因和HDAC的方式抑制CCA细胞中上皮调节因子的转录并阻断其极性。
High mobility group nucleosome-binding protein 3 (HMGN3), a member of the HMGN family, modulates the structure of chromatin and regulates transcription through transcription factors. HMGN3 has been implicated in the development of various cancers; however, the underlying mechanisms remain unclear. We herein demonstrated that the high expression of HMGN3 correlated with the metastasis of liver fluke infection-induced cholangiocarcinoma (CCA) in patients in northeastern Thailand. The knockdown of HMGN3 in CCA cells significantly impaired the oncogenic properties of colony formation, migration, and invasion. HMGN3 inhibited the expression of and blocked the intracellular polarities of epithelial regulator genes, such as the CDH1/E-cadherin and TJAP1 genes in CCA cells. A chromatin immunoprecipitation sequencing analysis revealed that HMGN3 required the transcription factor SNAI2 to bind to and repress the expression of epithelial regulator genes, at least in part, due to histone deacetylases (HDACs), the pharmacological inhibition of which reactivated these epithelial regulators in CCA, leading to impairing the cell migration capacity. Therefore, the overexpression of HMGN3 represses the transcription of and blocks the polarities of epithelial regulators in CCA cells in a manner that is dependent on the SNAI2 gene and HDACs.