An actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis
Dysfunction of cell cycle control and defects of primary ciliogenesis are two features of many cancers. Whether these events are interconnected and the driving mechanism controlling and coordinating these events remains largely unknown. Here we identified an actin branching surveillance system that alerts cells for the insufficiency of the actin branching network controlling the restriction point, cytokinesis, and primary ciliogenesis. We found that the ciliopathy protein Oral-Facial-Digital syndrome 1 (OFD1) functions as a previously undescribed class II NPF to promote Arp2/3 complex-mediated actin branching synergistically with class I NPF via its C-terminal acidic domain. Perturbation of actin branching promotes OFD1 degradation and inactivation via a liquid-to-gel transition at centriolar satellites. Elimination of OFD1 or disruption of OFD1-Arp2/3 interaction promotes ciliogenesis and drives proliferating, non-transformed cells into quiescence by an RB-dependent mechanism that is independent of ciliogenesis, senescence, or centrosome loss, which could be reversed by oncogene overactivation. Oncogene-transformed cells, as well as most cancer cells, bypass the G1/S checkpoint in the absence of OFD1 but fail to assemble actin filaments on the actomyosin ring, resulting in incomplete cytokinesis and irreversible mitotic catastrophe. Inhibition of OFD1 leads to marked suppression of pancreatic, colon, and triple-negative breast cancer cell growth in mouse xenograft models. Thus, cancer cells display a major difference from normal cells in their response to the OFD1-mediated actin branching surveillance system, and targeting this surveillance system provides a new direction for cancer therapy. Overall design: Comparison of gene expression profiling analysis of RNA-seq data for hTERT-RPE1-TOShOFD1 cells (a lentivirus-delivered Tet-On inducible knockdown RPE1 cell line with doxycycline (DOX) induced initiation of short hairpin RNA (shOFD1) expression against OFD1) treated with 200 ng/mL Doxycycline for 72 hours or not.