PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer

Jerfiz D. Constanzo, Ke jing Tang, Smita Rindhe, Margherita Melegari, Hui Liu, Ximing Tang, Jaime Rodriguez-Canales, Ignacio Wistuba, Pier Paolo Scaglioni

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)282-293
Number of pages12
JournalNeoplasia (United States)
Volume18
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Focal Adhesion Protein-Tyrosine Kinases
Non-Small Cell Lung Carcinoma
Focal Adhesions
Cytoskeleton
DNA Repair
Protein Inhibitors of Activated STAT
Neoplasms
Cytoplasm
Clustered Regularly Interspaced Short Palindromic Repeats
Apoptosis
Genes
Ubiquitin-Protein Ligases
Oxidative Phosphorylation
Ionizing Radiation
Cell Nucleus
Heterografts
Cell Communication
Protein-Tyrosine Kinases
DNA Damage
Cell Movement

ASJC Scopus subject areas

  • Cancer Research

Cite this

PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer. / Constanzo, Jerfiz D.; Tang, Ke jing; Rindhe, Smita; Melegari, Margherita; Liu, Hui; Tang, Ximing; Rodriguez-Canales, Jaime; Wistuba, Ignacio; Scaglioni, Pier Paolo.

In: Neoplasia (United States), Vol. 18, No. 5, 01.05.2016, p. 282-293.

Research output: Contribution to journalArticle

Constanzo, JD, Tang, KJ, Rindhe, S, Melegari, M, Liu, H, Tang, X, Rodriguez-Canales, J, Wistuba, I & Scaglioni, PP 2016, 'PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer', Neoplasia (United States), vol. 18, no. 5, pp. 282-293. https://doi.org/10.1016/j.neo.2016.03.003
Constanzo, Jerfiz D. ; Tang, Ke jing ; Rindhe, Smita ; Melegari, Margherita ; Liu, Hui ; Tang, Ximing ; Rodriguez-Canales, Jaime ; Wistuba, Ignacio ; Scaglioni, Pier Paolo. / PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer. In: Neoplasia (United States). 2016 ; Vol. 18, No. 5. pp. 282-293.
@article{a9b90a14a0af44fe9ba3eea300c58204,
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.",
author = "Constanzo, {Jerfiz D.} and Tang, {Ke jing} and Smita Rindhe and Margherita Melegari and Hui Liu and Ximing Tang and Jaime Rodriguez-Canales and Ignacio Wistuba and Scaglioni, {Pier Paolo}",
year = "2016",
month = "5",
day = "1",
doi = "10.1016/j.neo.2016.03.003",
language = "English (US)",
volume = "18",
pages = "282--293",
journal = "Neoplasia (United States)",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer

AU - Constanzo, Jerfiz D.

AU - Tang, Ke jing

AU - Rindhe, Smita

AU - Melegari, Margherita

AU - Liu, Hui

AU - Tang, Ximing

AU - Rodriguez-Canales, Jaime

AU - Wistuba, Ignacio

AU - Scaglioni, Pier Paolo

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85017376540&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017376540&partnerID=8YFLogxK

U2 - 10.1016/j.neo.2016.03.003

DO - 10.1016/j.neo.2016.03.003

M3 - Article

VL - 18

SP - 282

EP - 293

JO - Neoplasia (United States)

JF - Neoplasia (United States)

SN - 1522-8002

IS - 5

ER -