Figure S2 from FADD Functions as an Oncogene in Chr11q13.3-Amplified Head and Neck Squamous Cell Carcinoma

Zheng, Yang; Chen, Yinan; Meng, Xiaoyan; Zhang, Li; Ma, Yanni; Zhou, Rong; Fu, Shuiting; Chen, Heng; Xuanyuan, Xinyang; Jiang, Ruixin; Hou, Pengcong; Song, Xiaomeng; Wang, Yanqiu; Sun, Jingjing; Zhang, Wuchang; Li, Jiang; Liu, Zhonglong; Zhang, Zhiyuan; Zeng, Hanlin; He, Yue

doi:10.1158/0008-5472.29071812

Figure S2 from FADD Functions as an Oncogene in Chr11q13.3-Amplified Head and Neck Squamous Cell Carcinoma

journal contribution

posted on 2025-05-15, 12:52 authored by Yang Zheng, Yinan Chen, Xiaoyan Meng, Li Zhang, Yanni Ma, Rong Zhou, Shuiting Fu, Heng Chen, Xinyang Xuanyuan, Ruixin Jiang, Pengcong Hou, Xiaomeng Song, Yanqiu Wang, Jingjing Sun, Wuchang Zhang, Jiang Li, Zhonglong Liu, Zhiyuan Zhang, Hanlin Zeng, Yue He

Correlation between CNA and mRNA Expression Observed in TCGA Datasets

Funding

National Key Research and Development Program of China (NKPs)

National Natural Science Foundation of China (NSFC)

Innovative Research Team of High-level Local University in Shanghai (Innovative Research Team of High-level Local Universities in Shanghai)

The Jiangsu Province Higher Education Institutions Fundamental Science (Natural Science) Major Projects

Shanghai Clinical Research Center for Oral Diseases

Shanghai’s Top Priority Research Center

CAMS Innovation Fund for Medical Sciences

Shanghai Municipal Key Clinical Specialty

History

ARTICLE ABSTRACT

Chromosomal 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 adapter 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 the DNA helicase complex inhibitor and CDK4/6 inhibitor effectively curtailed tumor growth. Overall, this study identified a nonclassic oncogenic role for FADD in mediating tumor progression in HNSCC and provided a feasible treatment option for patients with chr11q13.3 amplification.Significance: FADD promotes progression of tumors with chr11q13.3 amplification by binding to the DNA helicase complex, which can be targeted in combination with cyclin D1 as a viable therapeutic strategy for HNSCC patients.