β4-integrins safeguard nuclear mechanics to suppress prostate cancer progression
- 1Department of General and Medical Biochemistry, Faculty of Biology, University of Gdansk
Abstract
Prostate cancer (PCa) progression is accompanied by profound alterations in cell-extracellular matrix (ECM) adhesion, nuclear architecture and mechanical adaptability, yet the molecular mechanisms linking these processes remain poorly understood. Hemidesmosomes (HDs), formed by 6{beta}4-integrins, anchor epithelial cells to the basement membrane and couple extracellular forces to the intermediate filament (IF) cytoskeleton. Here, we identify a previously unrecognized tumor-suppressive function of {beta}4-integrins in preserving nuclear integrity in prostate epithelial cells. Loss of {beta}4-integrins disrupted the cytokeratin-5 network and its coupling to the nucleus, leading to nuclear softening, lamin remodeling, reduced heterochromatin content and enhanced confined migration. Unexpectedly, proximity-labeling proteomics revealed that {beta}4-integrins engage nuclear pore complex (NPC) components in an 6-independent manner, particularly upon HD disassembly. Selected interactions were validated using proximity ligation and co-immunoprecipitation assays. {beta}4-integrin loss was associated with enlarged nuclear pores and aberrant nucleocytoplasmic transport, including nuclear accumulation of YAP1. Consistent with these findings, reduced {beta}4-integrin expression in a large PCa tissue cohort correlated with altered nuclear morphology, adverse clinicopathological features, metastatic progression, and poor patient survival. Collectively, our study establishes {beta}4-integrins as a critical molecular link between cell-ECM adhesion, nuclear mechanics and genome integrity.
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BibTeX
@misc{schmidt2026β4integrins,
title = {{β4-integrins safeguard nuclear mechanics to suppress prostate cancer progression}},
author = {A. Schmidt and R. Wei and P. Nastaly and M. Mehnaz-Enamul and A. Agashe and M. Rychlowski and K. Bury and S. Koivusalo and Q. Zhang and C. Frascogna and C. F. Natale and X. Yang and A. Jarmakowicz and A. Ahtikoski and M. Vaarala and X. Liu and K. Ruckemann-Dziurdzinska and M. Varjosalo and E. Bryl and A. Nain and G.-H. Wei and T. Wenta and A. Manninen},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748477},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748477v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - β4-integrins safeguard nuclear mechanics to suppress prostate cancer progression
AU - A. Schmidt
AU - R. Wei
AU - P. Nastaly
AU - M. Mehnaz-Enamul
AU - A. Agashe
AU - M. Rychlowski
AU - K. Bury
AU - S. Koivusalo
AU - Q. Zhang
AU - C. Frascogna
AU - C. F. Natale
AU - X. Yang
AU - A. Jarmakowicz
AU - A. Ahtikoski
AU - M. Vaarala
AU - X. Liu
AU - K. Ruckemann-Dziurdzinska
AU - M. Varjosalo
AU - E. Bryl
AU - A. Nain
AU - G.-H. Wei
AU - T. Wenta
AU - A. Manninen
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748477
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748477v1
AB - Prostate cancer (PCa) progression is accompanied by profound alterations in cell-extracellular matrix (ECM) adhesion, nuclear architecture and mechanical adaptability, yet the molecular mechanisms linking these processes remain poorly understood. Hemidesmosomes (HDs), formed by 6{beta}4-integrins, anchor epithelial cells to the basement membrane and couple extracellular forces to the intermediate filament (IF) cytoskeleton. Here, we identify a previously unrecognized tumor-suppressive function of {beta}4-integrins in preserving nuclear integrity in prostate epithelial cells. Loss of {beta}4-integrins disrupted the cytokeratin-5 network and its coupling to the nucleus, leading to nuclear softening, lamin remodeling, reduced heterochromatin content and enhanced confined migration. Unexpectedly, proximity-labeling proteomics revealed that {beta}4-integrins engage nuclear pore complex (NPC) components in an 6-independent manner, particularly upon HD disassembly. Selected interactions were validated using proximity ligation and co-immunoprecipitation assays. {beta}4-integrin loss was associated with enlarged nuclear pores and aberrant nucleocytoplasmic transport, including nuclear accumulation of YAP1. Consistent with these findings, reduced {beta}4-integrin expression in a large PCa tissue cohort correlated with altered nuclear morphology, adverse clinicopathological features, metastatic progression, and poor patient survival. Collectively, our study establishes {beta}4-integrins as a critical molecular link between cell-ECM adhesion, nuclear mechanics and genome integrity.
ER -