Abstract 1375: Paranuclear retention of c-KIT by Merkel cell polyomavirus large T-antigen suppresses autophagy through interaction with Beclin 1 essential for Merkel cell carcinoma cell survival

Abstract

Abstract Merkel cell carcinoma (MCC) is a very aggressive skin cancer most commonly caused by Merkel cell polyomavirus (MCPyV). While the strong expression of the human proto-oncogene c-KIT in MCC is well established, the functional relevance of this expression is unknown. Here, we demonstrate that paranuclear presence of c-KIT suppresses autophagy which is essential for maintenance of MCC cells. Specifically, after its phosphorylation, c-KIT traffics by clathrin-dependent endocytosis to late endosomes where it is sequestered in the paranuclear compartment by the MCPyV-encoded large transforming antigen (LT) via its Vam6p binding site, which also blocks c-KIT's lysosomal degradation. In this paranuclear compartment, c-KIT interacts directly with both the BH3 and the evolutionarily conserved domain (ECD) of Beclin 1, decreasing its binding to VPS34 and increasing its binding to BCL2, resulting in suppression of autophagy. Indeed, silencing of c-KIT induces autophagy and apoptosis in MCPyV-positive MCC cell lines. It is noteworthy that the positive feedback loop of LT and c-KIT also applies in the reverse direction, as LT is degraded via autophagy. This notion explains why an autophagy-inducing peptide efficiently induces apoptosis-independent cell death and inhibits tumor growth of MCC xenografts in mice. In conclusion, we identified a novel mechanism of MCPyV LT to suppress autophagy through sequestering and stabilizing c-KIT in the paranuclear compartment, which is mandatory to maintain the oncogenic phenotype of MCC cells. Autophagy-inducing agents therefore represent a therapeutic strategy for patients with advanced MCPyV-associated MCC. Citation Format: Hao Shi, Yajie Yang, Catharina Larsson, Weng-Onn Lui. Paranuclear retention of c-KIT by Merkel cell polyomavirus large T-antigen suppresses autophagy through interaction with Beclin 1 essential for Merkel cell carcinoma cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1375.