Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression

Despite critical roles in development and cancer, the mechanisms that specify invasive cellular behavior are poorly understood. Through a screen of transcription factors in Caenorhabditis elegans, we identified G1 cell-cycle arrest as a precisely regulated requirement of the anchor cell (AC) invasion program. We show that the nuclear receptor nhr-67/tlx directs the AC into G1 arrest in part through regulation of the cyclin-dependent kinase inhibitor cki-1. Loss of nhr-67 resulted in non-invasive, mitotic ACs that failed to express matrix metalloproteinases or actin regulators and lack invadopodia, F-actin-rich membrane protrusions that facilitate invasion. We further show that G1 arrest is necessary for the histone deacetylase HDA-1, a key regulator of differentiation, to promote pro-invasive gene expression and invadopodia formation. Together, these results suggest that invasive cell fate requires G1 arrest and that strategies targeting both G1-arrested and actively cycling cells may be needed to halt metastatic cancer. [Display omitted] •NHR-67/TLX maintains the C. elegans invasive anchor cell (AC) in G1 arrest•Mitotic ACs downregulate CKI-1/p21CIP1 and fail to invade•Mitotic ACs express early markers but lack differentiated invasive genes•Downstream of G1 arrest, invasive differentiation requires the HDAC, HDA-1 Functional links between cell-cycle arrest and invasive behavior have been difficult to show in vivo. Here, Matus et al. use C. elegans to demonstrate that cell invasion is a differentiated cellular state that requires G1 arrest, regulated by the transcription factor NHR-67/TLX and HDAC-mediated changes in gene expression.