Abstract
Early diagnosis of nasopharyngeal carcinoma (NPC) is difficult because of a lack of specific symptoms. Many patients have advanced disease at diagnosis, and these patients respond poorly to treatment. New treatments are therefore needed to improve the outcome of NPC. To better understand the molecular pathogenesis of NPC, here we used an NPC cell line in a genome-wide CRISPR-based knockout screen to identify the cellular factors and pathways essential for NPC (i.e. dependence factors). This screen identified the Moz, Ybf2/Sas3, Sas2, Tip60 histone acetyl transferase complex, NF-κB signaling, purine synthesis, and linear ubiquitination pathways; and MDM2 proto-oncogene as NPC dependence factors/pathways. Using gene knock out, complementary DNA rescue, and inhibitor assays, we found that perturbation of these pathways greatly reduces the growth of NPC cell lines but does not affect growth of SV40-immortalized normal nasopharyngeal epithelial cells. These results suggest that targeting these pathways/proteins may hold promise for achieving better treatment of patients with NPC.
Highlights
Diagnosis of nasopharyngeal carcinoma (NPC) is difficult because of a lack of specific symptoms
Complementary DNA rescue, and inhibitor assays, we found that perturbation of these pathways greatly reduces the growth of NPC cell lines but does not affect growth of SV40-immortalized normal nasopharyngeal epithelial cells
Nasopharyngeal carcinoma (NPC)4 occurs in the nasopharynx that is behind the nose and above the oropharynx
Summary
Genome-wide CRISPR screens were used to identify NPC genes essential for their growth and survival. KAT7 knockout significantly reduced BRD1, IKBKB, MDM2, OTULIN, RBCK1, ATIC, IKBKG, and PIK3C3 expression in C17 cells (Fig. 2F; *, p Ͻ 0.05; **, p Ͻ 0.01). KAT7 knockout significantly reduced CHUK, IKBKB, MDM2, and RBCK1 expression in NP69 cells (Fig. 2G; *, p Ͻ 0.05; **, p Ͻ 0.01). These data suggest that KAT7 can contribute NPC cell growth and survival through up-regulation of NPC-essential genes. OTULIN depletion greatly reduced C666-1 growth and had no effect on NP69 (Fig. 6G; **, p Ͻ 0.01) Because both the positive and negative regulators of linear ubiquitination were essential, the balance between the two events must be critical for NPC cell growth. Knockout significantly decreased C666-1 cell growth while having no effect on NP69 cell growth (Fig. S5B; **, p Ͻ 0.01)
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