2. Academic Validation
  3. Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway

Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway

  • Antioxidants (Basel). 2021 Nov 26;10(12):1898. doi: 10.3390/antiox10121898.
Chiao-Yun Lin 1,  Chen-Bin Chang 1 2,  Ren-Chin Wu 3,  Angel Chao 1 2,  Yun-Shien Lee 4,  Chi-Neu Tsai 5,  Chih-Hao Chen 6,  Chih-Feng Yen 2,  Chia-Lung Tsai 7
Affiliations

Affiliations

  • 1 Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
  • 2 Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
  • 3 Department of Pathology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
  • 4 Department of Biotechnology, Ming-Chuan University, Taoyuan 333, Taiwan.
  • 5 Department of Surgery, Graduate Institute of Clinical Medical Sciences, Chang-Gung University, New Taipei Municipal Tucheng Hospital, New Taipei City 236, Taiwan.
  • 6 Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Keelung, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
  • 7 Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
PMID: 34942999 DOI: 10.3390/antiox10121898
Abstract

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.

Keywords

KEAP1; LSD1; NRF2; endometrial cells; p62.

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