ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/039/SRR32362639/SRR32362639_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/038/SRR32362638/SRR32362638_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/035/SRR32362635/SRR32362635_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/036/SRR32362636/SRR32362636_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/035/SRR32362635/SRR32362635_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/039/SRR32362639/SRR32362639_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/038/SRR32362638/SRR32362638_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/037/SRR32362637/SRR32362637_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/037/SRR32362637/SRR32362637_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR323/036/SRR32362636/SRR32362636_1.fastq.gzprimaryOK200GenomicsDepartment of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospitalhttps://www.ebi.ac.uk/ena/browser/view/PRJNA1224430Homo sapiensChromosomal 11q13.3 amplification is the most common gene copy number variation event in head and neck squamous cell carcinoma (HNSCC) that corresponds with poor prognosis. Although cyclin D1, a G1/S phase cell cycle regulatory protein at this locus, is considered as a key driver of malignant progression, further exploration is needed to develop more effective targets for cases with this amplification. Using CRISPR-based gene knockout screening of genes located in chr11q13.3, we found that loss of the gene encoding the Fas-associated death domain (FADD) protein, a well-recognized adaptor to caspase-8 that induces cell apoptosis, significantly reduced cancer cell proliferation. FADD expression was elevated in chr11q13.3 amplified tumors and correlated with poor prognosis. RNA-sequencing, mass spectrometry, and proteomics analyses revealed a direct relationship between FADD and the DNA helicase MCM5 in the S phase. FADD and cyclin D1 acted at different stages of the cell cycle to synergistically induce proliferation, and caspase-8 deficiency was required for the oncogenic activity of FADD. In a patient-derived xenograft model with chr11q13.3 amplification, combined administration of DNA helicase complex inhibitor and CDK4/6 inhibitor effectively curtailed tumor growth. Overall, this study identified a non-classical oncogenic role for FADD in mediating tumor progression in HNSCC and provided a feasible treatment option for patients with chr11q13.3 amplification. Overall design: RNA-seq profiling in HN4 cell stably transfected with full-length FADD or control.ENAfalseFADD Functions as an Oncogene in Chr11q13.3 Amplified Head and Neck Squamous Cell CarcinomaFADD Functions as an Oncogene in Chr11q13.3 Amplified Head and Neck Squamous Cell Carcinoma2025-09-242025-02-22PRJNA1224430GSE2897409606