Merkel Cell Polyomavirus Small T Antigen Activates Noncanonical NF-κB Signaling to Promote Tumorigenesis
- 3 August 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 18 (11), 1623-1637
- https://doi.org/10.1158/1541-7786.MCR-20-0587
Abstract
Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence- associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NF-kappa B (ncNF-kappa B), instead of canonical NF-kappa B signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-kappa B signaling both by inducing H3K4 trimethylation-mediated increases of NF-kappa B2 and RELB transcription and also by promoting NF kappa B2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-kappa B signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sTexpressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-kappa B pathway activation and SASP gene expression, and the inhibition of ncNF-kappa B signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT-induced ncNF-kappa B signaling as an essential tumorigenic pathway in MCC.Other Versions
Funding Information
- ACS (RSG-18-058-01)
- NIAMS (R01AR072655)
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