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

Chiao-Yun Lin,Angel Chao,Yun-Shien Lee,Chia-Lung Tsai,Chi-Neu Tsai,Chen-Bin Chang,Ren-Chin Wu,Chih-Feng Yen,Chih-Hao Chen

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.

Highlights

lysine-specific demethylase 1 (LSD1) protein levels were elevated in high glucose media (Supplementary Figure S1)
LSD1 decreased in p62-suppressed cell lines (Figure 1C; Supplementary Figure S3A), and ubiquitinated LSD1 increased in the presence of p62 siRNA (Figure 1D)
We found that an everolimus, TAKinib, PF-670462, and sotrastaurin can block the expression levels of LSD1, nuclear factor erythroid 2-related factor 2 (NRF2), and phosphorylated p62 (Figure 3C–F)

Summary

Introduction

Endometrial cancer (EC) originates from epithelial layer of uterus cavity, and its incidence and mortality increased between 1990 to 2017 [1]. Most patients with endometrial cancer are postmenopausal women, and only about 14% of patients are 40 years of age or younger [2]. The main risk factor is endogenous estrogen or estrogen-like drugs used in hormone therapy, such as tamoxifen, which cause endometrial cell pathology [3]. Some metabolic abnormalities such as obesity-associated hyperglycemia [4], hypertension [5], and hyperlipidemia [6] are considered risk factors of endometrial cancer. Patients with high blood sugar have an increased risk of developing breast cancer, hepatocellular carcinoma, pancreatic cancer, colorectal cancer, bladder cancer, Antioxidants 2021, 10, 1898.

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Results

Conclusion