Abstract 3457: CYLD regulates cGAS-STING pathway and metastasis in HNSCC

Abstract Chromosomal instability, a hallmark of cancer, is related to cancer progression including metastasis and known to promote the activation of the cGAS-STING pathway. Cylindromatosis (CYLD), a well-known negative regulator of NF-kappaB, is down-regulated in aggressive head and neck squamous cell carcinoma (HNSCC), correlating with reduced apoptosis, enhanced invasiveness, and poor prognosis of patients with HNSCC. However, its role in metastasis, immune responses and interaction with the cGAS-STING pathway remain unclear. We found that CYLD protein was rapidly up-regulated and phosphorylated under Poly(dA:dT) or cGAMP stimulation. In addition, by using various cancer cell lines expressing shRNA targeting CYLD, we found that CYLD was essential for sustained phosphorylation of TBK1, a main STING downstream mediator. These results suggest that modulation of the CIN-related activation of cGAS-STING pathway and hence immune responses by down-regulation of CYLD regulates HNSCC progression. Further studies focusing on possible relationship between the NF-kappaB and cGAS-STING pathways would contribute to better understanding of the molecular mechanisms underlying CIN-related metastasis. Furthermore, our preliminary data revealed that CYLD knockdown significantly enhanced metastasis of murine HNSCC cells in immunocompetent mice. Citation Format: Shiyang Deng, Satoru Shinriki, Yasuhito Tanaka, Hideki Nakayama. CYLD regulates cGAS-STING pathway and metastasis in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3457.