DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer.
Technol Cancer Res Treat
; 22: 15330338231167249, 2023.
Article
em En
| MEDLINE
| ID: mdl-37365941
ABSTRACT
OBJECTIVES:
DOT1L, a histone methylase, is overexpression in renal cell cancer. However, the role and detailed molecular mechanism of DOT1L involved in renal cancer development remain unknown.METHODS:
The inhibition of DOT1L was used by SGC0946 and short hairpin RNA silencing. Monodansylcadaverine staining and transmission electron microscope were performed to detect autophagy changes as a result of the inhibition of DOT1L. MitoTracker Red assay was used to analyze mitochondrial morphology. The autophagy markers and mitochondria-related proteins were analyzed by Western blot, qPCR, or immunofluorescence. ChIP assay was performed to demonstrate H3K79me2 is involved in the direct regulation of Farnesoid X receptor transcription.RESULTS:
DOT1L inhibition increased autophagy activity and promoted mito chondria fusion in cell lines of renal cancer. Inhibition of DOT1L upregulated levels of LC3α/ß, P62, MFN1, and MFN2, which contributed to autophagy activity or mitochondria fusion. DOT1L knockdown showed a similar the above process. DOT1L inhibition or silencing resulted in AMP-activated protein kinase activation and mammalian target of rapamycin inhibition. Mechanistically, the DOT1L inhibitor and its short hairpin RNAs decreased the expression of Farnesoid X receptor in a histone methylase-dependent manner.CONCLUSION:
We revealed the essential role of Farnesoid X receptor in regulating DOT1L-induced autophagy and mitochondrial fission through the AMP-activated protein kinase/mammalian target of rapamycin pathway in cell lines of renal cancer, which may provide new insights into the pathogenesis of renal cell cancer.Palavras-chave
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Bases de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Renais
/
Neoplasias Renais
Limite:
Humans
Idioma:
En
Revista:
Technol Cancer Res Treat
Assunto da revista:
NEOPLASIAS
/
TERAPEUTICA
Ano de publicação:
2023
Tipo de documento:
Article