Merkel Cell Polyomavirus Small T Antigen Activates Noncanonical NF-κB Signaling to Promote Tumorigenesis

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• Merkel cell polyomavirus (MCPyV) is linked to Merkel cell carcinoma (MCC), a rare skin cancer.
• Human polyomaviruses (HPyVs) can infect skin, but MCPyV is the only one associated with cancer.
• MCPyV small T antigen (sT) plays a role in viral oncogenesis.

Purpose of the Study:

• To investigate the mechanism by which MCPyV sT contributes to MCC development.
• To elucidate the role of NF-κB signaling pathways in MCPyV-induced cellular transformation.
• To identify potential therapeutic targets for MCC.

Main Methods:

• Analysis of HPyV6, HPyV7, and MCPyV sT expression in cell models.
• Investigation of NF-κB signaling activation (canonical vs. noncanonical).
• Assessment of senescence evasion, SASP induction, and cell proliferation.
• Analysis of ncNF-κB pathway activation in MCC cell lines and tumors.
• Inhibition of ncNF-κB signaling in vitro and in vivo xenograft models.

Main Results:

• MCPyV sT, unlike HPyV6/7 sTs, activated noncanonical NF-κB (ncNF-κB) signaling to evade p53-mediated senescence.
• MCPyV sT stabilized NFKB2 and RELB transcription via H3K4 trimethylation and FBXW7 inhibition.
• ncNF-κB signaling drove senescence-associated secretory phenotype (SASP) cytokine secretion, promoting autocrine cell proliferation.
• Virus-positive MCC tumors and cell lines exhibited ncNF-κB activation and SASP.
• Inhibiting ncNF-κB signaling suppressed MCC cell growth in vitro and in xenografts.

Conclusions:

• MCPyV sT-induced ncNF-κB activation is a key driver of MCC tumorigenesis.
• This is the first study to identify ncNF-κB signaling activation by any polyomavirus.
• Targeting the ncNF-κB pathway represents a potential therapeutic strategy for MCC.