PRMT1 Inhibition Targets BNC1-Dependent Proliferation in Squamous Cell Carcinoma

Abstract

Transcription factor complexes integrate diverse signals into discrete physiological outputs and are often aberrantly regulated in malignancies such as squamous cell carcinoma (SCC). In this study, we sought to discover new transcriptional complexes essential for SCC tumor maintenance, which have catalytic activities that can be targeted to provide new therapeutic options for patients with SCC. Comparing expression patterns of SCC tumors with those of non-SCC tumors, we have identified basonuclin 1 as a highly expressed, SCC-specific transcription factor. Analysis of direct transcriptional targets has uncovered an essential role for basonuclin 1 in controlling the proliferation–differentiation–migration axis. Basonuclin 1 activates proliferation genes while repressing a FRA1-dependent promigratory program and IRF6-dependent differentiation program. In addition, basonuclin 1 physically interacts with PRMT1 (protein arginine methyltransferase 1) to activate cell cycle genes. Importantly, proliferation can be blocked in SCC tumors using PRMT1 inhibitors, which has no effect on the repression of promigratory genes. Given the diverse gene expression programs regulated by transcription factors, this work demonstrates that protumorigenic activities can be specifically targeted through the inhibition of cofactors without activating pathways that may lead to tumor progression.