Abstract A28: Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma

Abstract

Abstract Although NGLY1 is known as a pivotal enzyme that catalyzes the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. While studying the NGLY1 deficiency-caused neurodevelopmental variations in patients with a congenital deglycosylation disorder, we made an intriguing discovery that the expression of NGLY1 appears to be dysregulated in human melanoma cells. We have examined how NGLY1 expression affects viability, tumor growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumors. NGLY1 knockdown caused melanoma cell death and tumor growth retardation. Targeting NGLY1 in melanoma cells induced pleiotropic responses, predominantly stress signaling-associated apoptosis and cytokine surges, which synergize with the antimelanoma activity of standard chemotherapy and targeted therapy agents. Pharmacologic and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel antimelanoma strategy with the opportunity of a broad therapeutic window. Citation Format: Victor Lin, Ashwini Zolekar, Nigam Mishra, Yin Ying Ho, Hamed Hayatshahi, Abhishek Parab, Rohit Sampat, Xiaoyan Liao, Peter Hoffmann, Jin Liu, Kyle Emmitte, Yu-Chieh Wang. Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A28.