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Collagen 6A3 ( Col6a3 ), a component of extracellular matrix, is often up-regulated in tumours and is believed to play a pro-oncogenic role. However the mechanisms of its tumorigenic activity are poorly understood. We show here that  Col6a3  is highly expressed in densely growing mouse embryonic fibroblasts (MEFs). In MEFs where the TAF4 subunit of general transcription factor IID (TFIID) has been inactivated, elevated  Col6a3  expression prevents contact inhibition promoting their 3 dimensional growth as foci and fibrospheres. Analyses of gene expression in densely growing  Taf4 −/−   MEFs revealed repression of the Hippo pathway and activation of Wnt signalling. The Hippo activator Kibra/Wwc1 is repressed under dense conditions in  Taf4 −/−   MEFs, leading to nuclear accumulation of the proliferation factor YAP1 in the cells forming 3D foci. At the same time,  Wnt9a  is activated and the  Sfrp2  antagonist of Wnt signalling is repressed. Surprisingly, treatment of  Taf4 −/−   MEFs with all-trans retinoic acid (ATRA) restores contact inhibition suppressing 3D growth. ATRA represses  Col6a3  expression independently of TAF4 expression and  Col6a3  silencing is sufficient to restore contact inhibition in  Taf4 −/−   MEFs and to suppress 3D growth by reactivating Kibra expression to induce Hippo signalling and by inducing  Sfrp2  expression to antagonize Wnt signalling. All together, these results reveal a critical role for  Col6a3  in regulating both Hippo and Wnt signalling to promote 3D growth, and show that the TFIID subunit TAF4 is essential to restrain the growth promoting properties of  Col6a3 . Our data provide new insight into the role of extra cellular matrix components in regulating cell growth.

TAF4 Inactivation Reveals the 3 Dimensional Growth Promoting Activities of Collagen 6A3