Journal
FASEB JOURNAL
Volume 36, Issue 7, Pages -Publisher
WILEY
DOI: 10.1096/fj.202200386R
Keywords
epithelial mesenchymal transition; histone deacetylase; HMGN; liver fluke; transcription factor
Categories
Funding
- NSRF under the Basic Research Fund of Khon Kaen University under through Cholangiocarcinoma Research Institute (CARI), an Invitation research grant from the Faculty of Medicine, Khon Kaen University [IN62237]
- MEXT of Japan [18H02842, 21H02952]
- CARI [07/2560]
- JASSO of Japan
- Grants-in-Aid for Scientific Research [21H02952, 18H02842] Funding Source: KAKEN
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This study found that the high expression of high mobility group nucleosome-binding protein 3 (HMGN3) is correlated with the metastasis of cholangiocarcinoma (CCA). HMGN3 inhibits the expression of epithelial regulator genes by binding with the transcription factor SNAI2 and regulating histone deacetylases (HDACs), thereby affecting the migration capacity of CCA cells.
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.
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