β4-integrins safeguard nuclear mechanics to suppress prostate cancer progression

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 α6β4-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 β4-integrins in preserving nuclear integrity in prostate epithelial cells. Loss of β4-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 β4-integrins engage nuclear pore complex (NPC) components in an α6-independent manner, particularly upon HD disassembly. Selected interactions were validated using proximity ligation and co-immunoprecipitation assays. β4-integrin loss was associated with enlarged nuclear pores and aberrant nucleocytoplasmic transport, including nuclear accumulation of YAP1. Consistent with these findings, reduced β4-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 β4-integrins as a critical molecular link between cell-ECM adhesion, nuclear mechanics and genome integrity. SIGNIFICANCE β4-integrins interact with nuclear pore complexes revealing nucleoprotective function. Their loss disrupts cytokeratin architecture, alters lamin balance, nuclear transport, and chromatin regulation, providing a mechanism by which β4-integrin loss promotes prostate tumorigenesis.