Examining the Role of Chromatin Remodeler skp-1(snw1) During C. elegans Anchor Cell Invasion

Cellular invasion is a fundamental feature of cancer

metastasis. We utilize a unique in vivo model, studying the process of anchor cell (AC) invasion into the vulval epithelium during C. elegans development as a model for cellular invasion. Previous studies investigating the conserved transcription factor (TF) NHR-67 and a histone deacetylase as crucial to the differentiated cell behavior with genome modification and arrest observed in an invading AC.

 

To identify additional chromatin modifiers that mediate

invasion, we are conducting a tissue-specific RNAi screen using a commercially available ORF library. Thus far, we have screened 70 genes annotated as chromatin regulators and have implicated 6 genes in AC invasion. We have further investigated the gene skp-1, of which the mammalian homolog, SNW1, has been studied in the context of oncogenesis. To characterize the function of skp-1 in AC invasion, we have utilized a cell cycle biosensor providing a visual readout of cell cycle state live. Our findings demonstrate that RNAi mediated depletion of skp-1 results in cycling, non-invasive ACs. In addition, we created an improved RNAi vector, which has increased the penetrance of invasion defects, using available cDNA sequences. We have identified the interaction of skp-1 with hlh-2, a conserved transcription factor in the gene regulatory network promoting invasion. Using quantitative measures of endogenous protein levels paired with perturbation analyses, we identify the upstream regulation of hlh-2 activity by skp-1. Together, the results identify novel pro-invasive genes and provide possible therapeutic targets to limit invasiveness in disease states.