Myocardin-Related Transcription Factors and SRF are required for cytoskeletal dynamics, invasion and experimental metastasis

Abstract

Rho GTPases control cytoskeletal dynamics through cytoplasmic effectors, and regulate transcriptional activation by the Myocardin Related Transcription Factors (MRTFs), coactivators for Serum Response Factor (SRF). We used RNAi to investigate the contribution of the MRTF-SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, where basal MRTF-SRF activity is Rho-dependent. Depletion of MRTFs or SRF reduces cell adhesion, spreading, invasion and motility in culture, without affecting proliferation or inducing apoptosis; MRTF-depleted tumor cell xenografts exhibit reduced cell motility but proliferate normally. MRTF- and SRF-depleted tumor cells fail to colonise the lung from the bloodstream, being unable to persist following their initial arrival at the lung. Only a few genes exhibit MRTF-dependent expression in both cell lines. Two of these, MYH9 (MLC2) and MYL9 (NMHCIIa), are also required for invasion and lung colonisation. Conversely, expression of an activated MRTF increases lung colonisation by poorly metastatic B16F0 cells. Actin-based cell behaviour and experimental metastasis thus requires Rho-dependent nuclear signalling through the MRTF-SRF network.