A non‐metabolic function of hexokinase 2 in small cell lung cancer: promotes cancer cell stemness by increasing USP11‐mediated CD133 stability

作者：Juhong Wang, Fei Shao, Yannan Yang, Wei Wang, Xueying Yang, Renda Li, Hong Cheng, Sijin Sun, Xiaoli Feng, Yibo Gao, Jie He, Zhimin Lu · 发表于：癌症：英文版 · 年份：2022 · DOI：10.1002/cac2.12351 · 被引用次数：89 · 研究领域：Cancer, Hypoxia, and Metabolism、Cancer Cells and Metastasis、Glycosylation and Glycoproteins Research

Abstract Background Maintenance of cancer stem‐like cell (CSC) stemness supported by aberrantly regulated cancer cell metabolism is critical for CSC self‐renewal and tumor progression. As a key glycolytic enzyme, hexokinase 2 (HK2) plays an instrumental role in aerobic glycolysis and tumor progression. However, whether HK2 directly contribute to CSC stemness maintenance in small cell lung cancer (SCLC) is largely unclear. In this study, we aimed to investgate whether HK2 independent of its glycolytic activity is directly involved in stemness maintenance of CSC in SCLC. Methods Immunoblotting analyses were conducted to determine the expression of HK2 in SCLC CSCs and their differentiated counterparts. CSC‐like properties and tumorigenesis of SCLC cells with or without HK2 depletion or overexpression were examined by sphere formation assay and xenograft mouse model. Immunoprecipitation and mass spectrometry analyses were performed to identify the binding proteins of CD133. The expression levels of CD133‐associated and CSC‐relevant proteins were evaluated by immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry assay. RNA expression levels of Nanog , POU5F1 , Lin28 , HK2 , Prominin‐1 were analyzed through quantitative reverse transcription PCR. Polyubiquitination of CD133 was examined by in vitro or in vivo ubiquitination assay. CD133 + cells were sorted by flow cytometry using an anti‐CD133 antibody. Results We demonstrated that HK2 expression was mu...