TY - JOUR
T1 - Merkel cell polyomavirus small T antigen activates noncanonical NF-kB signaling to promote tumorigenesis
AU - Zhao, Jiawei
AU - Jia, Yuemeng
AU - Shen, Shunli
AU - Kim, Jiwoong
AU - Wang, Xun
AU - Lee, Eunice
AU - Brownell, Isaac
AU - Cho-Vega, Jeong Hee
AU - Lewis, Cheryl
AU - Homsi, Jade
AU - Sharma, Rohit R.
AU - Wang, Richard C.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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-kB (ncNF-kB), instead of canonical NF-kB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-kB 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-kB 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-kB pathway activation and SASP gene expression, and the inhibition of ncNF-kB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT-induced ncNF-kB signaling as an essential tumorigenic pathway in MCC. Implications: This work is the first to identify the activation of ncNF-kB signaling by any polyomavirus and its critical role in MCC tumorigenesis.
AB - 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-kB (ncNF-kB), instead of canonical NF-kB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-kB 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-kB 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-kB pathway activation and SASP gene expression, and the inhibition of ncNF-kB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT-induced ncNF-kB signaling as an essential tumorigenic pathway in MCC. Implications: This work is the first to identify the activation of ncNF-kB signaling by any polyomavirus and its critical role in MCC tumorigenesis.
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U2 - 10.1158/1541-7786.MCR-20-0587
DO - 10.1158/1541-7786.MCR-20-0587
M3 - Article
C2 - 32753470
AN - SCOPUS:85100392095
SN - 1541-7786
VL - 18
SP - 1623
EP - 1637
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 11
ER -