Enhanced O-GlcNAc modification induced by the RAS/MAPK/CDK1 pathway is required for SOX2 protein expression and generation of cancer stem cells

• Published in: Scientific reports Vol. 12; no. 1; p. 2910
• Main Authors: Shimizu, Masahiro, Shibuya, Hiroshi, Tanaka, Nobuyuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/395; 631/67/71; 631/80/86/2368; Acetylglucosamine - metabolism; Animals; Antineoplastic Agents; Cancer; Carcinogenesis - drug effects; Carcinogenesis - genetics; CDC2 Protein Kinase - metabolism; Cell differentiation; Cell self-renewal; Cyclic N-Oxides - pharmacology; Cyclin-dependent kinases; Embryo fibroblasts; Enzyme Inhibitors - pharmacology; Fibroblasts; Gene Expression; Humanities and Social Sciences; Humans; Indolizines - pharmacology; MAP kinase; Mice; Mitogen-Activated Protein Kinases - metabolism; multidisciplinary; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; NF-κB protein; O-GlcNAcylation; p53 Protein; Pyridinium Compounds - pharmacology; Ras protein; ras Proteins - metabolism; Repopulation; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Somatic cells; Sox2 protein; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stem cell transplantation; Stem cells; Therapeutic targets; Tumor cell lines; Tumor suppressor genes; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-06916-y

Cancer stem cells (CSCs) have tumour initiation, self-renewal, and long-term tumour repopulation properties, and it is postulated that differentiated somatic cells can be reprogrammed to CSCs by oncogenic signals. We previously showed that oncogenic HRAS V12 conferred tumour initiation capacity in tumour suppressor p53-deficient ( p53 −/− ) primary mouse embryonic fibroblasts (MEFs) through transcription factor NF-κB-mediated enhancement of glucose uptake; however, the underlying mechanisms of RAS oncogene-induced CSC reprogramming have not been elucidated. Here, we found that the expression of the reprogramming factor SOX2 was induced by HRAS V12 in p53 −/− MEFs. Moreover, gene knockout studies revealed that SOX2 is an essential factor for the generation of CSCs by HRAS V12 in mouse and human fibroblasts. We demonstrated that HRAS V12 -induced cyclin-dependent kinase 1 (CDK1) activity and subsequent enhancement of protein O -GlcNAcylation were required for SOX2 induction and CSC generation in these fibroblasts and cancer cell lines containing RAS mutations. Moreover, the CDK inhibitor dinaciclib and O -GlcNAcylation inhibitor OSMI1 reduced the number of CSCs derived from these cells. Taken together, our results reveal a signalling pathway and mechanism for CSC generation by oncogenic RAS and suggest the possibility that this signalling pathway is a therapeutic target for CSCs.