Integrative Multi-Omics Analysis Identifies a Functional Enhancer Driving Tumorigenesis in Head and Neck Squamous Cell Carcinoma

Xu, P.; Liu, X.; Yang, P.; Tran, N. L.; Pu, J.; Lu, X.; Lee, V.; Wang, Y. E.; Jiang, Q.; Yu, D.; Song, J.; Zhong, Q.; Guan, X.; Su, Y.-X.; Wang, J.

doi:10.64898/2026.02.03.703438

bioRxiv · 10.64898/2026.02.03.703438

Integrative Multi-Omics Analysis Identifies a Functional Enhancer Driving Tumorigenesis in Head and Neck Squamous Cell Carcinoma

Xu, P.·Liu, X.·Yang, P.·Tran, N. L.·Pu, J.·Lu, X.·Lee, V.·Wang, Y. E.·Jiang, Q.·Yu, D.·Song, J.·Zhong, Q.·Guan, X.·Su, Y.-X.·Wang, J.

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Abstract

Enhancer is a critical epigenetic feature in head and neck squamous cell carcinoma (HNSCC), yet the functional roles of individual enhancers remain poorly understood. Here, we conducted an integrative multi-omics analysis based on publicly available ATAC-seq, H3K27ac ChIP-seq, transcriptomic profiling, and genetic association datasets to systematically map HNSCC-associated enhancers and their target genes. Integrating ATAC-seq and H3K27ac ChIP-seq, we identified 20,362 enhancers and 18,040 enhancer-associated genes, highlighting widespread regulatory complexity. Functional characterization of the TERT-associated enhancer GH05J001312 (GRCh38/hg38: chr5:1312099-1317743) revealed strong transcriptional activity in HNSCC. CRISPR-mediated deletion of a core sequence significantly reduced TERT expression, impaired cellular proliferation in vitro, and suppressed tumor growth in vivo, confirming its role as a key cis-regulatory element. RNA-seq analysis of enhancer-edited cells uncovered 742 differentially expressed genes enriched in cancer-related pathways, including MAPK and IL-17 signaling, indicating a broad transcriptional impact. Collectively, our findings establish GH05J001312 as a functional enhancer driving oncogenic programs in HNSCC and suggest enhancer-targeted strategies as a potential therapeutic avenue.

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Xu, P., Liu, X., Yang, P., Tran, N. L., Pu, J., Lu, X., Lee, V., Wang, Y. E., Jiang, Q., Yu, D., Song, J., Zhong, Q., Guan, X., Su, Y.-X., Wang, J.. 2026-02-05. Integrative Multi-Omics Analysis Identifies a Functional Enhancer Driving Tumorigenesis in Head and Neck Squamous Cell Carcinoma. https://doi.org/10.64898/2026.02.03.703438

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