ArticleJournal of experimental & clinical cancer research : CR2023
Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer.
Article in Journal of experimental & clinical cancer research : CR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Weaning drives microbiome-mediated epigenetic regulation to shape immune memory in mice.Nature microbiology · 2026Article
- Epigenome editing based treatment: Progresses and challenges.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- Chemoresistance in the era of immunotherapy: challenges and novel combinatorial strategies for digestive system tumors.Frontiers in immunology · 2026Review
- Senescence-associated and immune-related 9p21.3 locus genes in colorectal cancer: epigenetic architecture, molecular landscape and therapeutic possibilities.Frontiers in cell and developmental biology · 2026Review
- Global burden of colorectal cancer in 2022 and projections to 2050: incidence and mortality estimates from GLOBOCAN.BMC cancer · 2025Article
- Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.Nature reviews. Cancer · 2025Review
- Cadmium and Chromium exposure associated with DNA hypermethylation of p16 tumor suppressor gene: a case-control study from endemic region of northern India.Clinical epigenetics · 2025Article
- The Potential Role ofMicroorganisms · 2025Review
- DNA methylation profiling at base-pair resolution reveals unique epigenetic features of early-onset colorectal cancer in underrepresented populations.Clinical epigenetics · 2025Article
- Aging and tumors: a dynamic interaction.Discover oncology · 2025Review
- Clinicopathologic and Molecular Characterization of Colorectal Cancer in Patients Aged ≥80 years.Clinical interventions in aging · 2025Article
- Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024Review
- Research progress of DNA methylation in colorectal cancer (Review).Molecular medicine reports · 2024Review
- Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives.MedComm · 2024Review
- Article
- Dietary Folate and Cofactors Accelerate Age-dependent p16 Epimutation to Promote Intestinal Tumorigenesis.Cancer research communications · 2024Article
- Association of APC Expression with Its Promoter Methylation Status and the Prognosis of Hepatocellular Carcinoma.Asian Pacific journal of cancer prevention : APJCP · 2023Article
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundMethylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.
methodsWe established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA sequencing (RNA-seq), quantitative PCR, and flow cytometry. We performed single-cell RNA sequencing (scRNA-seq) to characterize tumor-infiltrating immune cells throughout tumor progression. We tested whether anti-PD-L1 immunotherapy affects overall survival of tumor-bearing mice and whether inhibition of both epigenetic regulation and immune checkpoint is more efficacious.
resultsMice carrying combined Apc mutation and p16 epimutation had significantly shortened survival and increased tumor growth compared to those with Apc mutation only. Intriguingly, colon tumors with p16 epimutation exhibited an activated interferon pathway, increased expression of programmed death-ligand 1 (Pdl1), and enhanced infiltration of immune cells. scRNA-seq further revealed the presence of Foxp3
conclusionsOur study demonstrated that age-dependent p16 epimutation creates a permissive microenvironment for malignant transformation of polyps to colon cancer. Our findings provide a mechanistic rationale for future targeted therapy in patients with p16 epimutation.
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