title: PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer.
abstract: The sequence of genomic alterations acquired by cancer cells during tumor progression and metastasis is poorly understood. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates cytoskeleton remodeling, mitogenic signaling and cell survival. FAK has previously been reported to undergo nuclear localization during cell migration, cell differentiation and apoptosis. However, the mechanism behind FAK nuclear accumulation and its contribution to tumor progression has remained elusive. We report that amplification of FAK and the SUMO E3 ligase PIAS1 gene loci frequently co-occur in non-small cell lung cancer (NSCLC) cells, and that both gene products are enriched in a subset of primary NSCLCs. We demonstrate that endogenous FAK and PIAS1 proteins interact in the cytoplasm and the cell nucleus of NSCLC cells. Ectopic expression of PIAS1 promotes proteolytic cleavage of the FAK C-terminus, focal adhesion maturation and FAK nuclear localization. Silencing of PIAS1 deregulates focal adhesion turnover, increases susceptibility to apoptosis in vitro and impairs tumor xenograft formation in vivo. Nuclear FAK in turn stimulates gene transcription favoring DNA repair, cell metabolism and cytoskeleton regulation. Consistently, ablation of FAK by CRISPR/Cas9 editing, results in basal DNA damage, susceptibility to ionizing radiation and impaired oxidative phosphorylation. Our findings provide insight into a mechanism regulating FAK cytoplasm-nuclear distribution and demonstrate that FAK activity in the nucleus promotes NSCLC survival and progression by increasing cell-ECM interaction and DNA repair regulation.
authors.affiliation: Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: Jerfiz D
authors.initials: JD
authors.lastname: Constanzo
authors.affiliation: Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center Dallas, TX, USA; Department of Pulmonary Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Ke-Jing
authors.initials: KJ
authors.lastname: Tang
authors.affiliation: Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Rindhe
authors.affiliation: Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: Margherita
authors.initials: M
authors.lastname: Melegari
authors.affiliation: Department of Translational Molecular Pathology, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Translational Molecular Pathology, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Translational Molecular Pathology, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Thoracic, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center Dallas, TX, USA. Electronic address: Pier.Scaglioni@UTSouthwestern.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni