Enhanced O-GlcNAc modification induced by the RAS/MAPK/CDK1 pathway is required for SOX2 protein expression and generation of cancer stem cells
Open accessAbstract
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 HRASV12 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 HRASV12 in p53−/− MEFs. Moreover, gene knockout studies revealed that SOX2 is an essential factor for the generation of CSCs by HRASV12 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.
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In RAS-mutant colorectal cancer, macropinocytosis is upregulated, and these cancer cells exhibit sensitivity to MP inhibitors.
“In RAS-mutant colorectal cancer, MP is indeed upregulated, and these cancer cells exhibit sensitivity to MP inhibitors [28,30].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [28]
RAS mutations and the PI3K pathway contribute to macropinocytosis activation.
“RAS mutations and the PI3K pathway contribute to MP activation.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [28]
Oncogenic RAS mutations induce cancer stem cell formation by activating CDK1 and promoting O-GlcNAcylation of proteins, which upregulates SOX2 expression.
“oncogenic RAS mutations induce cancer stem cell formation by activating CDK1 and promoting O-GlcNAcylation of proteins, which upregulates SOX2 expression, a key factor in CSC generation [28]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [28]
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- Authors
- Shimizu, M., Shibuya, H., & Tanaka, N.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Nippon Medical School (JP)
- Corresponding author
- Tanaka, Nobuyuki
- Venue
- Scientific Reports
- Published
- 2022-02-21
- Volume
- 12
- Issue
- 1
- Pages
- 2910-2910
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8861017
- OpenAlex
- W4212919370
- Cited by
- 18
- References
- 72
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 2 · 2022: 6
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science (19K16782, 17H04554)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- cancer stem cells, O-GlcNAcylation, SOX2, cyclin-dependent kinase 1, dinaciclib, therapeutic target
- MeSH terms
- Acetylglucosamine, Animals, Antineoplastic Agents, Cyclic N-Oxides, Enzyme Inhibitors, Humans, Indolizines, Pyridinium Compounds, Neoplastic Stem Cells, Signal Transduction, Gene Expression, CDC2 Protein Kinase, ras Proteins, Mitogen-Activated Protein Kinases, Mice, SOXB1 Transcription Factors, Carcinogenesis
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