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

Abstract

SUMMARY 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.

miR-8 modulates cytoskeletal regulators to influence cell survival and epithelial organization in Drosophila wings

“…This may explain why the rescue of “undead” miR-8 expressing cells with P35 leads to tissue folding but not the more extreme phenotypes of tissue invasiveness or tumorigenesis as reported in P35-rescue contexts where cell cycle defects lead to aneuploidy (Dekanty et al, 2012). Indeed a prolonged G2 phase helps prevent aneuploidy and limits cell delamination in Drosophila wings (Dekanty et al, 2015), and recent work in C. elegans also confirms that blocking the cell cycle in G2 constrains cell migration (Matus et al, 2015). We suggest that the G2 elongation and arrest observed in miR-8 expressing cells may actually serve a protective function, in limiting cell invasiveness and migration.…”

Conserved and Exapted Functions of Nuclear Receptors in Animal Development

“…During the L2 and L3 stages, nhr-67 functions in the differentiation of pre-VU and anchor cells of the ventral uterus [152]. Defective anchor cells fail to invade the underlying vulval tissue and remain in the cell cycle, generating additional cells [153]. Later in larval development, it plays a role in vulval morphogenesis [154] and in the male it regulates the timing of the migration of the linker cell, which is the male equivalent of the anchor cell [155].…”

A pilgrim's progress: Seeking meaning in primordial germ cell migration

“…The conflict between migration and proliferation of PGC was also described in the developing reproductive tract of C. elegans , where the anchor cells are only capable of invading into the vulval epithelium during G1/G0 cell cycle arrest (Matus et al ., 2015). Induction of proliferation in these normally quiescent cells blocks their invasive function.…”