Nuclear fascin regulates cancer cell survival

TY - JOUR

T1 - Nuclear fascin regulates cancer cell survival

AU - Lawson, Campbell D

AU - Peel, Samantha

AU - Jayo Andres, Asier

AU - Corrigan, Adam

AU - Iyer, Preeti

AU - Baxter Dalrymple, Mabel

AU - Marsh, Richard J

AU - Cox, Susan

AU - van Audenhove, Isabel

AU - Gettemans, Jan

AU - Parsons, Maddy

N1 - Funding Information: We are grateful to Steve Lynham (King’s College London Proteomics Facility) for assistance with proteomics experiments and to Dave Smith (AstraZeneca) for assistance with the small molecule compound library. The authors would also like to thank Angus Lamond (University of Dundee) and Hiroshi Kimura for generously providing plasmids for this study. The authors are also grateful to Simon Ameer-Beg and Conor Treacy (King’s College London) for assistance with FLIM. CL and RJM are funded by the Medical Research Council UK (MR/R008264/1, to MP). MBD is funded by Cancer Research UK (City of London Centre Studentships award C7893/A31530, to MP). Publisher Copyright: © Lawson et al.

PY - 2022/8/30

Y1 - 2022/8/30

N2 - 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 DDR. 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 tumourigenesis and provide insight into potential pathways for targeted fascin-dependent cancer cell killing.

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 DDR. 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 tumourigenesis and provide insight into potential pathways for targeted fascin-dependent cancer cell killing.

UR - http://www.scopus.com/inward/record.url?scp=85136846820&partnerID=8YFLogxK

U2 - 10.7554/eLife.79283

DO - 10.7554/eLife.79283

M3 - Article

SN - 2050-084X

VL - 11

JO - eLife

JF - eLife

M1 - e79283

ER -