Merkel Cell Polyomavirus Small T Antigen Activates Noncanonical NF-κB Signaling to Promote Tumorigenesis
Jiawei Zhao, Yuemeng Jia, Shunli Shen, Jiwoong Kim, Xun Wang, Eunice Lee, Isaac Brownell, Jeong Hee Cho‐Vega, Cheryl Lewis, Jade Homsi, Rohit Sharma, Richard C. Wang
Abstract
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-κB (ncNF-κB), instead of canonical NF-κB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-κB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-κB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT–expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-κB pathway activation and SASP gene expression, and the inhibition of ncNF-κB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT–induced ncNF-κB signaling as an essential tumorigenic pathway in MCC. Implications: This work is the first to identify the activation of ncNF-κB signaling by any polyomavirus and its critical role in MCC tumorigenesis.