NUSAP1 regulates rheumatoid arthritis fibroblast-like synoviocyte phenotypes implicated in joint damage, glycolysis, and a cancer-associated transcriptomic signature

The fibroblast-like synoviocyte (FLS) has a central role in rheumatoid arthritis (RA) pathogenesis and its invasive behavior strongly correlates with disease severity and joint damage. Yet, the regulation of FLS invasiveness has been incompletely characterized. The nucleolar and spindle associated protein 1 (NUSAP1) gene has been implicated in cancer cell invasion and outcomes, and we considered that it might also be involved in the regulation of FLS invasiveness. siRNA was used to knockdown NUSAP1 in RA FLS, compared with a control siRNA. Cells were then studied in invasion, migration, proliferation and adhesion assays, and RNA was used for RNA sequencing and for both pathway and co-expression network analyses. siRNA knockdown of NUSAP1 significantly reduced RA FLS invasiveness ( P = 0.002) and migration in the scratch/wound healing assay ( P = 0.024). RNA sequencing analyses revealed that NUSAP1 knockdown significantly affected processes implicated in different types of cancer and in cancer biology, including cell cycle, DNA replication, transcription, RHO GTPase signaling, regulation of cytokinesis and cell metabolism pathways, including glycolysis. Among the genes with the most significantly decreased expression in FLS knocked down for NUSAP1 were ARHGAP11A, ANLN, PRC1 and RACGAP1, four genes previously implicated in cancer invasion and migration, and eighteen kinesin family genes, including KIF1c, known to regulate FLS invasion. We describe a new role for NUSAP1 in the regulation of the RA FLS invasiveness, migration, and glycolysis, all relevant to disease pathogenesis and joint damage, and identify a new transcriptomic signature regulated by this gene. These findings raise the possibility that NUSAP1, or one of its target genes and pathways may become a new prognostic marker or target for new therapies for RA. • The fibroblast-like synoviocyte (FLS) has a central role in rheumatoid arthritis (RA) pathogenesis and its invasive behavior strongly correlates with disease severity and joint damage. • Here we describe a new role for the nucleolar and spindle associated protein 1 (NUSAP1) gene in the regulation of RA FLS invasiveness and glycolysis. • We also identify new cellular processes and pathways regulated by NUSAP1.