ArticleJournal of experimental & clinical cancer research : CR2025
Genome-wide CRISPR screening identifies PHF8 as an effective therapeutic target for KRAS- or BRAF-mutant colorectal cancers.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Discovery of a novel and potent KRASJournal of enzyme inhibition and medicinal chemistry · 2026Article
- Review
- Methyltransferase MGMT upregulation drives metastasis by activating epithelial-mesenchymal transition in KRAS mutant colon cancer.Cell death & disease · 2026Article
- Identification of mitochondrial associated genes as diagnostic biomarkers for basal cell carcinoma: Comprehensive bioinformatics analysis and experimental validation.Glycoconjugate journal · 2026Article
- Review
- DNA, RNA, and histone methylation regulation enzymes and their crosstalk in colorectal carcinogenesis and progression: a review of molecular mechanisms, clinical implications, and future perspectives.Cellular & molecular biology letters · 2025Review
- Applications of Genome-wide Screening of CRISPR/Cas9 Knockout Library in Identifying Novel Molecular Targets for Xenobiotics.Environment & health (Washington, D.C.) · 2025Review
- Elucidation of novel diagnostic biomarkers and therapeutic targets in colorectal carcinoma: an integrative approach leveraging multi-omics, computational biology, and single-cell sequencing technologies.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Review
- Demystifying the Role of Histone Demethylases in Colorectal Cancer: Mechanisms and Therapeutic Opportunities.Current issues in molecular biology · 2025Review
- Discovery and structural studies of histone demethylases.Frontiers in epigenetics and epigenomics · 2025Review
- CRISPR/Cas9 in colorectal cancer: Revolutionizing precision oncology through genome editing and targeted therapeutics.Iranian journal of basic medical sciences · 2025Review
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Authors and funding
11 authors.
Funding
Abstract
backgroundMutations in KRAS and BRAF genes are prevalent in colorectal cancer (CRC), which strikingly promote tumorigenesis and lead to poor response to a variety of treatments including immunotherapy by activating the MAPK/ERK pathway. Thus, there is an urgent need to discover effective therapeutic targets and strategies.
methodsCRISPR-Cas9 lentiviral knockout library was used to screen the suppressors of anti-PD1 immunotherapy. Bioinformatic analysis was used to analyze the correlation between PHF8 expression and immune indicators in CRC. In vitro and in vivo experiments were utilized to determine the effects of PHF8 on the immune indexes and malignant phenotypes of CRC cells. qRT-PCR, western blotting, immunohistochemical (IHC) staining, and chromatin immunoprecipitation (ChIP)-qPCR assays were used to determine the regulatory effects of PHF8 on PD-L1, KRAS, BRAF, and c-Myc and the regulatory effect c-Myc/miR-22-3p signaling axis on PHF8 expression in CRC cells.
resultsThis study identified histone lysine demethylase PHF8 as a negative regulator for the efficacy of anti-PD1 therapy and found that it was highly expressed in CRCs and strongly associated with poor patient survival. Functional studies showed that PHF8 played an oncogenic role in KRAS- or BRAF-mutant CRC cells, but not in wild-type ones. Mechanistically, PHF8 up-regulated the expression of PD-L1, KRAS, BRAF, and c-Myc by increasing the levels of transcriptional activation marks H3K4me3 and H3K27ac and decreasing the levels of transcriptional repression mark H3K9me2 within their promoter regions, promoting immune escape and tumor progression. Besides, our data also demonstrated that PHF8 was up-regulated by the c-Myc/miR-22-3p signaling axis to form a positive feedback loop. Targeting PHF8 substantially improved the efficacy of anti-PD1 therapy and inhibited the malignant phenotypes of KRAS- or BRAF-mutant CRC cells.
conclusionOur data demonstrate that PHF8 may be an effective therapeutic target for KRAS- or BRAF-mutant CRCs.
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