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Kit-mediated autophagy suppression driven by a viral oncoprotein emerges as a crucial survival mechanism in Merkel

Hao Shi1, Yajie Yang1, Jiwei Gao1,2

  • 1Department of Oncology-Pathology, Karolinska Institutet; BioClinicum J6:20, Karolinska University Hospital, Solna, Sweden.

Autophagy
|March 20, 2025
PubMed

Insights

Merkel cell carcinoma (MCC) cells rely on KIT and viral oncoproteins for survival by suppressing autophagy. Stimulating autophagy effectively kills MCC cells and inhibits tumor growth, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Virology
  • Cell Biology

Background:

  • Merkel cell carcinoma (MCC) is an aggressive skin cancer often linked to Merkel cell polyomavirus (MCPyV).
  • Overexpression of the KIT proto-oncogene is common in MCC, contributing to its aggressive nature.

Purpose of the Study:

  • To investigate the interplay between MCPyV large T-antigen (LT) and KIT in regulating autophagy in MCC.
  • To explore the therapeutic potential of modulating autophagy in MCC.

Main Methods:

  • Investigated the interaction between MCPyV LT, KIT, and autophagy-related proteins (VPS39, BECN1, BCL2, PIK3C3).
  • Utilized KIT depletion, autophagy inhibition (3-MA, bafilomycin A1), and autophagy stimulation in MCC cell lines.
  • Assessed cell death, apoptosis, LT expression, and tumor growth in MCC xenograft mouse models.

Main Results:

  • MCPyV LT stabilizes KIT, sequestering it via VPS39, which suppresses autophagy by altering BECN1 and PIK3C3 complex interactions.
  • KIT depletion triggers autophagy and apoptosis, reducing LT levels; blocking autophagy rescues apoptosis in KIT-depleted cells.
  • Autophagy stimulation significantly increases MCC cell death and inhibits tumor growth in vivo.

Conclusions:

  • MCPyV LT manipulates autophagy through KIT stabilization, essential for MCC cell survival.
  • Targeting autophagy represents a promising therapeutic strategy for advanced MCPyV-associated MCC.
Keywords:
AutophagyBECN1KITMerkel cell carcinomaMerkel cell polyomaviruslarge T antigen

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