Oncolytic Newcastle disease virus promotes tumor cell apoptosis through SUMO-1-dependent PRKN-mediated degradation of c-Myc
The oncogenic transcription factor c-Myc is aberrantly upregulated in many cancers and plays a central role in tumor cell proliferation and survival. However, direct pharmacological targeting of c-Myc remains challenging because of its intrinsically disordered structure. Newcastle disease virus (NDV) is an oncolytic virus with selective antitumor activity, but the molecular mechanisms by which NDV disrupts oncogenic signaling remain incompletely understood. Here, we show that NDV induces apoptosis in multiple tumor cell lines and suppresses tumor growth in an A549 xenograft model. NDV infection markedly reduced c-Myc protein levels in tumor cells in a time- and dose-dependent manner, and c-Myc knockdown further enhanced NDV-induced intrinsic apoptosis. Mechanistically, NDV promoted ubiquitin-proteasome-dependent degradation of c-Myc through ubiquitination at Lys142. Screening of candidate E3 ubiquitin ligases identified PRKN as a key mediator of NDV-induced c-Myc degradation. NDV infection induced SUMO-1-dependent nuclear translocation of PRKN, allowing PRKN to interact with nuclear c-Myc and promote its degradation. Disruption of this pathway by SUMO-1 or PRKN knockdown impaired PRKN nuclear accumulation, restored c-Myc stability, and attenuated NDV-induced apoptosis. Functionally, expression of the degradation-resistant c-Myc K142R mutant or restoration of c-Myc in c-Myc-knockdown cells protected tumor cells from NDV-induced apoptosis. Together, these findings identify a SUMO-1-PRKN-c-Myc signaling axis that mediates NDV-induced tumor cell apoptosis and reveal c-Myc destabilization as an important mechanism underlying the oncolytic activity of NDV.