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.
Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA. Electronic address: david.matus@stonybrook.edu.
David Q
DQ
Matus
Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA.
Lauren L
LL
Lohmer
Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA.
Laura C
LC
Kelley
Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA.
Adam J
AJ
Schindler
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA.
Abraham Q
AQ
Kohrman
Department of Life Sciences, Imperial College London, Imperial College Road SAF Building, London SW7 2AZ, UK.
Michalis
M
Barkoulas
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA.
Wan
W
Zhang
Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA.
Qiuyi
Q
Chi
Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA. Electronic address: david.sherwood@duke.edu.
David R
DR
Sherwood
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D000069261:Podosomes / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism
D000199:Actins; D029742:Caenorhabditis elegans Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C520004:Nhr-67 protein, C elegans; D018160:Receptors, Cytoplasmic and Nuclear; C115024:cki-1 protein, C elegans; C508305:HDA-1 protein, C elegans; D006655:Histone Deacetylases