JOURNAL ARTICLE

Merkel Cell Polyomavirus Small T Antigen Activates Non-Canonical 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 R Sharma, Richard C Wang
Molecular Cancer Research: MCR 2020 August 4
32753470
Multiple human polyomaviruses (HPyVs) 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 non-canonical 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. Non-canonical 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 non-canonical NF-κB (ncNF-κB) signaling by any polyomavirus and its critical role in MCC tumorigenesis.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
32753470
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"