Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway
Endometrial cancer incidence increases annually. Several risk factors, including high glucose intake, are associated with endometrial cancer. We investigated whether glucose affects lysine-specific demethylase 1 (LSD1) expression and the responsible molecular mechanisms. A high concentration of gluc...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/12/1898 |
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| author | Chiao-Yun Lin Chen-Bin Chang Ren-Chin Wu Angel Chao Yun-Shien Lee Chi-Neu Tsai Chih-Hao Chen Chih-Feng Yen Chia-Lung Tsai |
| author_facet | Chiao-Yun Lin Chen-Bin Chang Ren-Chin Wu Angel Chao Yun-Shien Lee Chi-Neu Tsai Chih-Hao Chen Chih-Feng Yen Chia-Lung Tsai |
| author_sort | Chiao-Yun Lin |
| collection | DOAJ |
| description | Endometrial cancer incidence increases annually. Several risk factors, including high glucose intake, are associated with endometrial cancer. We investigated whether glucose affects lysine-specific demethylase 1 (LSD1) expression and the responsible molecular mechanisms. A high concentration of glucose stimulated p62 phosphorylation and increased LSD1 protein expression. Knockdown of p62 or treatment with mammalian target of rapamycin (mTOR), transforming growth factor-β activated kinase 1 (TAK1), casein kinase 1 (CK1), and protein kinase C (PKC) inhibitors abrogated glucose-regulated LSD1 expression. Unphosphorylated p62 and LSD1 formed a complex with Kelch-like ECH-associated protein 1 (KEAP1) and were degraded by the KEAP1-dependent proteasome. Phosphorylated p62 increased LSD1 protein expression by escaping the KEAP1 proteasome complex. LSD1 and KEAP1 interaction was enhanced in the presence of the nuclear factor erythroid 2-related factor 2 (NRF2) protein. LSD1 also participated in antioxidant gene regulation with NRF2. In diabetic mice, increasing LSD1and phospho-p62 expression was observed in uterine epithelial cells. Our results indicate that glucose induces p62 phosphorylation through mTOR, TAK1, CK1, and PKC kinases. Subsequently, phospho-p62 competitively interacts with KEAP1 and releases NRF2–LSD1 from the KEAP1 proteasome complex. Our findings may have public health implications for the prevention of endometrial cancer. |
| first_indexed | 2024-03-10T04:39:09Z |
| format | Article |
| id | doaj.art-fad9d31166c34131ae1c62b64556d4f5 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T04:39:09Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-fad9d31166c34131ae1c62b64556d4f52023-11-23T03:32:35ZengMDPI AGAntioxidants2076-39212021-11-011012189810.3390/antiox10121898Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 PathwayChiao-Yun Lin0Chen-Bin Chang1Ren-Chin Wu2Angel Chao3Yun-Shien Lee4Chi-Neu Tsai5Chih-Hao Chen6Chih-Feng Yen7Chia-Lung Tsai8Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, TaiwanGynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, TaiwanDepartment of Pathology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, TaiwanGynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, TaiwanDepartment of Biotechnology, Ming-Chuan University, Taoyuan 333, TaiwanDepartment of Surgery, Graduate Institute of Clinical Medical Sciences, Chang-Gung University, New Taipei Municipal Tucheng Hospital, New Taipei City 236, TaiwanDepartment of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Keelung, Chang Gung University College of Medicine, Taoyuan 333, TaiwanDepartment of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, TaiwanGenomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan 333, TaiwanEndometrial cancer incidence increases annually. Several risk factors, including high glucose intake, are associated with endometrial cancer. We investigated whether glucose affects lysine-specific demethylase 1 (LSD1) expression and the responsible molecular mechanisms. A high concentration of glucose stimulated p62 phosphorylation and increased LSD1 protein expression. Knockdown of p62 or treatment with mammalian target of rapamycin (mTOR), transforming growth factor-β activated kinase 1 (TAK1), casein kinase 1 (CK1), and protein kinase C (PKC) inhibitors abrogated glucose-regulated LSD1 expression. Unphosphorylated p62 and LSD1 formed a complex with Kelch-like ECH-associated protein 1 (KEAP1) and were degraded by the KEAP1-dependent proteasome. Phosphorylated p62 increased LSD1 protein expression by escaping the KEAP1 proteasome complex. LSD1 and KEAP1 interaction was enhanced in the presence of the nuclear factor erythroid 2-related factor 2 (NRF2) protein. LSD1 also participated in antioxidant gene regulation with NRF2. In diabetic mice, increasing LSD1and phospho-p62 expression was observed in uterine epithelial cells. Our results indicate that glucose induces p62 phosphorylation through mTOR, TAK1, CK1, and PKC kinases. Subsequently, phospho-p62 competitively interacts with KEAP1 and releases NRF2–LSD1 from the KEAP1 proteasome complex. Our findings may have public health implications for the prevention of endometrial cancer.https://www.mdpi.com/2076-3921/10/12/1898p62KEAP1LSD1NRF2endometrial cells |
| spellingShingle | Chiao-Yun Lin Chen-Bin Chang Ren-Chin Wu Angel Chao Yun-Shien Lee Chi-Neu Tsai Chih-Hao Chen Chih-Feng Yen Chia-Lung Tsai Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway Antioxidants p62 KEAP1 LSD1 NRF2 endometrial cells |
| title | Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway |
| title_full | Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway |
| title_fullStr | Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway |
| title_full_unstemmed | Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway |
| title_short | Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway |
| title_sort | glucose activates lysine specific demethylase 1 through the keap1 p62 pathway |
| topic | p62 KEAP1 LSD1 NRF2 endometrial cells |
| url | https://www.mdpi.com/2076-3921/10/12/1898 |
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