2. Academic Validation
  3. Kit-mediated autophagy suppression driven by a viral oncoprotein emerges as a crucial survival mechanism in Merkel cell carcinoma

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

  • Autophagy. 2025 Mar 19:1-21. doi: 10.1080/15548627.2025.2477385.
Hao Shi 1,  Yajie Yang 1,  Jiwei Gao 1 2,  Satendra Kumar 1,  Hong Xie 1 3,  Ziqing Chen 1,  Jiawen Lyu 1,  Harri Sihto 4,  Virve Koljonen 5,  Silvia Vega-Rubin-de-Celis 6,  Vladana Vukojevic 7,  Filip Farnebo 8,  Viveca Björnhagen 8,  Anders Höög 1 9,  C Christofer Juhlin 1 9,  Linkiat Lee 1,  Malin Wickström 10,  Jürgen C Becker 11 12,  John Inge Johnsen 10,  Catharina Larsson 1,  Weng-Onn Lui 1
Affiliations

Affiliations

  • 1 Department of Oncology-Pathology, Karolinska Institutet; BioClinicum J6:20, Karolinska University Hospital, Solna, Sweden.
  • 2 The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
  • 3 Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 4 Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • 5 Department of Plastic Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • 6 Institute for Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany.
  • 7 Laboratory of Experimental Alcohol and Drug Addiction Research, Department of Clinical Neuroscience, Karolinska Institutet; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • 8 Department of Molecular Medicine and Surgery, Karolinska Institutet; Clinic for Reconstructive Plastic Surgery, Karolinska University Hospital, Stockholm, Sweden.
  • 9 Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
  • 10 Department of Women's and Children's Health, Karolinska Institutet; BioClinicum J5:20, Karolinska University Hospital, Solna, Sweden.
  • 11 Translational Skin Cancer Research, University Medicine Essen, Essen, Germany.
  • 12 German Cancer Consortium (DKTK), German Cancer Research Institute (DKFZ), Heidelberg, Baden-Württemberg, Germany.
PMID: 40108758 DOI: 10.1080/15548627.2025.2477385
Abstract

The KIT/c-Kit proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin Cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/Autophagy by stabilizing and sequestering KIT in the paranuclear compartment via binding VPS39. KIT engaged with phosphorylated BECN1, thereby enhancing its association with BCL2 while diminishing its interaction with the PIK3C3 complex. This process ultimately resulted in the suppression of Autophagy. Depletion of KIT triggered both Autophagy and Apoptosis, and decreased LT expression. Conversely, blocking Autophagy in KIT-depleted cells restored LT levels and rescued Apoptosis. Additionally, stimulating Autophagy efficiently increased cell death and inhibited tumor growth of MCC xenografts in mice. These insights into the interplay between MCPyV LT and Autophagy regulation reveal important mechanisms by which viral oncoproteins are essential for MCC cell viability. Thus, autophagy-inducing agents represent a therapeutic strategy in advanced MCPyV-associated MCC.Abbreviation: 3-MA, 3-methyladenine; AL, autolysosome; AP, autophagosome; Baf-A1, bafilomycin A1; BARA, β-α repeated Autophagy specific domain; BH3, BCL2 homology 3 domain; CCD, coiled-coil domain; CHX, cycloheximide; Co-IP, co-immunoprecipitation; CQ, chloroquine; CTR, control; DAPI, 4',6-diamidino-2-phenylindole; EBSS, Earle's balanced salt solution; ECD, evolutionarily conserved domain; EEE, three-tyrosine phosphomimetic mutations Y229E Y233E Y352E; ER, endoplasmic reticulum; FFF, three-tyrosine non-phosphomimetic mutations; FFPE, formalin-fixed paraffin-embedded; FL, full-length; GIST, gastrointestinal stromal tumor; IB, immunoblotting; IHC, immunohistochemistry; KIT-HEK293, KIT stably expressing HEK293 cells; KRT20/CK20, keratin 20; LT, large T-antigen; LT339, MCPyV truncated LT antigen; LTco, codon-optimized MCPyV LT antigen; MCC, Merkel cell carcinoma; MCPyV-, MCPyV-negative; MCPyV, Merkel cell polyomavirus; MCPyV+, MCPyV-positive; PARP1, poly(ADP-ribose) polymerase 1; PCI, pan-caspase inhibitor; PI, propidium iodide; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; RB1, RB transcriptional corepressor 1; RTKs, receptor tyrosine kinases; KITLG/SCF, KIT ligand; sT, small T-antigen; sTco, codon-optimized MCPyV sT antigen; T-B, Tat-BECN1; T-S, Tat-scrambled; TEM, transmission electron microscopy.

Keywords

Autophagy; BECN1; KIT; Merkel cell carcinoma; Merkel cell polyomavirus; large T antigen.

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