ArticleThe Journal of clinical investigation2011
XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas.
Article in The Journal of clinical investigation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
38 citing papers in PubMed, 79 citations in OpenAlex.
- Mitochondria-Associated Pathways in Cancer and Precancerous Conditions: Mechanistic Insights.International journal of molecular sciences · 2025Review
- Generation and characterization of CRISPR-Cas9-mediated XPC gene knockout in human skin cells.Scientific reports · 2024Article
- Nucleotide excision repair gene polymorphisms and hepatoblastoma susceptibility in Eastern Chinese children: A five-center case-control study.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2024Article
- Article
- Diabetes and Cancer: A Twisted Bond.Oncology reviews · 2024Review
- Article
- Mitochondrial DNA Instability in Mammalian Cells.Antioxidants & redox signaling · 2022Review
- Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma.International journal of molecular sciences · 2022Review
- Elevated glucose increases genomic instability by inhibiting nucleotide excision repair.Life science alliance · 2021Article
- Epigenetic and metabolic interplay in cutaneous squamous cell carcinoma.Experimental dermatology · 2021Article
- Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype.International journal of molecular sciences · 2021Article
- Characterization of NADPH Oxidase Expression and Activity in Acute Myeloid Leukemia Cell Lines: A Correlation with the Differentiation Status.Antioxidants (Basel, Switzerland) · 2021Article
- Xeroderma Pigmentosum C: A Valuable Tool to Decipher the Signaling Pathways in Skin Cancers.Oxidative medicine and cellular longevity · 2021Review
- Imaging of metabolic activity adaptations to UV stress, drugs and differentiation at cellular resolution in skin and skin equivalents - Implications for oxidative UV damage.Redox biology · 2020Article
- PPRC1, but not PGC-1α, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts.Genetics and molecular biology · 2020Article
- Deciphering UV-induced DNA Damage Responses to Prevent and Treat Skin Cancer.Photochemistry and photobiology · 2020Review
- Xeroderma Pigmentosum C (XPC) Mutations in Primary Fibroblasts Impair Base Excision Repair Pathway and Increase Oxidative DNA Damage.Frontiers in genetics · 2020Article
- UVB-induced DHODH upregulation, which is driven by STAT3, is a promising target for chemoprevention and combination therapy of photocarcinogenesis.Oncogenesis · 2019Article
- Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.The British journal of dermatology · 2019Observational
- A Novel Drug Resistance Mechanism: Genetic Loss of Xeroderma Pigmentosum Complementation Group C (Frontiers in pharmacology · 2019Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
DNA damage is a well-known initiator of tumorigenesis. Studies have shown that most cancer cells rely on aerobic glycolysis for their bioenergetics. We sought to identify a molecular link between genomic mutations and metabolic alterations in neoplastic transformation. We took advantage of the intrinsic genomic instability arising in xeroderma pigmentosum C (XPC). The XPC protein plays a key role in recognizing DNA damage in nucleotide excision repair, and patients with XPC deficiency have increased incidence of skin cancer and other malignancies. In cultured human keratinocytes, we showed that lentivirus-mediated knockdown of XPC reduced mitochondrial oxidative phosphorylation and increased glycolysis, recapitulating cancer cell metabolism. Accumulation of unrepaired DNA following XPC silencing increased DNA-dependent protein kinase activity, which subsequently activated AKT1 and NADPH oxidase-1 (NOX1), resulting in ROS production and accumulation of specific deletions in mitochondrial DNA (mtDNA) over time. Subcutaneous injection of XPC-deficient keratinocytes into immunodeficient mice led to squamous cell carcinoma formation, demonstrating the tumorigenic potential of transduced cells. Conversely, simultaneous knockdown of either NOX1 or AKT1 blocked the neoplastic transformation induced by XPC silencing. Our results demonstrate that genomic instability resulting from XPC silencing results in activation of AKT1 and subsequently NOX1 to induce ROS generation, mtDNA deletions, and neoplastic transformation in human keratinocytes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.