RT Journal Article
SR Electronic
T1 Nuclear fascin regulates cancer cell survival
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.17.496538
DO 10.1101/2022.06.17.496538
A1 Campbell D. Lawson
A1 Samantha Peel
A1 Asier Jayo
A1 Adam Corrigan
A1 Preeti Iyer
A1 Mabel Baxter Dalrymple
A1 Richard J. Marsh
A1 Susan Cox
A1 Isabel Van Audenhove
A1 Jan Gettemans
A1 Maddy Parsons
YR 2022
UL http://biorxiv.org/content/early/2022/06/17/2022.06.17.496538.abstract
AB Fascin is an important regulator of F-actin bundling leading to enhanced filopodia assembly. Fascin is also overexpressed in most solid tumours where it supports invasion through control of F-actin structures at the periphery and nuclear envelope. Recently fascin has been identified in the nucleus of a broad range of cell types but the contributions of nuclear fascin to cancer cell behaviour remain unknown. Here we demonstrate that fascin bundles F-actin within the nucleus to support chromatin organisation and efficient DNA damage response. Fascin associates directly with phosphorylated Histone H3 leading to regulated levels of nuclear fascin to support these phenotypes. Forcing nuclear fascin accumulation through the expression of nuclear-targeted fascin-specific nanobodies or inhibition of Histone H3 kinases results in enhanced and sustained nuclear F-actin bundling leading to reduced invasion, viability and nuclear fascin-specific/driven apoptosis. These findings represent an additional important route through which fascin can support tumorigenesis and provide insight into potential pathways for targeted fascin-dependent cancer cell killing.Competing Interest StatementDeclaration of financial competing interest: JG is shareholder of the company Gulliver Biomed BV. JG declares that he has no non-financial competing interests. All other authors declare no competing financial interests.