Membrane-bound transcription factor LRRC4 inhibits glioblastoma cell motility

Membrane-bound transcription factors (MTFs) have been observed in many types of organisms, such as plants, animals and microorganisms. However, the routes of MTF nuclear translocation are not well understood. Here, we reported that LRRC4 is a novel MTF that translocates to the nucleus as a full-length protein via endoplasmic reticulum-Golgi transport, which is different from the previously described nuclear entry mechanism. A ChIP-seq assay showed that LRRC4 target genes were mainly involved in cell motility. We confirmed that LRRC4 bound to the enhancer element of the RAP1GAP gene to activate its transcription and inhibited glioblastoma cell movement by affecting cell contraction and polarization. Furthermore, atomic force microscopy (AFM) confirmed that LRRC4 or RAP1GAP altered cellular biophysical properties, such as the surface morphology, adhesion force and cell stiffness. Thus, we propose that LRRC4 is an MTF with a novel route of nuclear translocation. Our observations demonstrate that LRRC4-null glioblastoma led to disordered RAP1GAP gene expression, which increased cellular movement. Re-expression of LRRC4 enabled it to suppress tumors, and this is a potential for targeted treatment in glioblastoma.