Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in ß-Cells.
Int J Mol Sci
; 21(21)2020 Oct 29.
Article
in En
| MEDLINE
| ID: mdl-33137873
ABSTRACT
Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced ß-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the ß-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. ß-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Apoptosis
/
Insulin-Secreting Cells
/
Enhancer of Zeste Homolog 2 Protein
/
Insulin Secretion
/
Glucose
/
Lipids
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Year:
2020
Type:
Article