DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer
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 st...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2023-06-01
|
| Series: | Technology in Cancer Research & Treatment |
| Online Access: | https://doi.org/10.1177/15330338231167249 |
| _version_ | 1797773127577501696 |
|---|---|
| author | Yanguang Hou MD Jiachen Liu MD Shiyu Huang MD Lei Wang MD Juncheng Hu PhD Xiuheng Liu MD, PhD |
| author_facet | Yanguang Hou MD Jiachen Liu MD Shiyu Huang MD Lei Wang MD Juncheng Hu PhD Xiuheng Liu MD, PhD |
| author_sort | Yanguang Hou MD |
| collection | DOAJ |
| description | 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/β, 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. |
| first_indexed | 2024-03-12T22:00:47Z |
| format | Article |
| id | doaj.art-295a8f9535aa4129b8e045a2ad821082 |
| institution | Directory Open Access Journal |
| issn | 1533-0338 |
| language | English |
| last_indexed | 2024-03-12T22:00:47Z |
| publishDate | 2023-06-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Technology in Cancer Research & Treatment |
| spelling | doaj.art-295a8f9535aa4129b8e045a2ad8210822023-07-25T07:03:21ZengSAGE PublishingTechnology in Cancer Research & Treatment1533-03382023-06-012210.1177/15330338231167249DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal CancerYanguang Hou MD0Jiachen Liu MD1Shiyu Huang MD2Lei Wang MD3Juncheng Hu PhD4Xiuheng Liu MD, PhD5 Wuhan University Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China Wuhan University Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China Wuhan University Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China Department of Urology, , Wuhan, Hubei, People’s Republic of China Wuhan University Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China Department of Urology, , Wuhan, Hubei, People’s Republic of ChinaObjectives 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/β, 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.https://doi.org/10.1177/15330338231167249 |
| spellingShingle | Yanguang Hou MD Jiachen Liu MD Shiyu Huang MD Lei Wang MD Juncheng Hu PhD Xiuheng Liu MD, PhD DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer Technology in Cancer Research & Treatment |
| title | DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer |
| title_full | DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer |
| title_fullStr | DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer |
| title_full_unstemmed | DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer |
| title_short | DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer |
| title_sort | dot1l epigenetically regulates autophagy and mitochondria fusion in cell lines of renal cancer |
| url | https://doi.org/10.1177/15330338231167249 |
| work_keys_str_mv | AT yanguanghoumd dot1lepigeneticallyregulatesautophagyandmitochondriafusionincelllinesofrenalcancer AT jiachenliumd dot1lepigeneticallyregulatesautophagyandmitochondriafusionincelllinesofrenalcancer AT shiyuhuangmd dot1lepigeneticallyregulatesautophagyandmitochondriafusionincelllinesofrenalcancer AT leiwangmd dot1lepigeneticallyregulatesautophagyandmitochondriafusionincelllinesofrenalcancer AT junchenghuphd dot1lepigeneticallyregulatesautophagyandmitochondriafusionincelllinesofrenalcancer AT xiuhengliumdphd dot1lepigeneticallyregulatesautophagyandmitochondriafusionincelllinesofrenalcancer |