β4-integrins safeguard nuclear mechanics to suppress prostate cancer progression

Prostate cancer (PCa) progression is marked by significant changes in cell interaction with the extracellular matrix (ECM), nuclear structure, and mechanical resilience. Hemidesmosomes, composed of 6beta4-integrins, bind epithelial cells to the basement membrane, transmitting external forces to the intermediate filament (IF) cytoskeleton. Researchers have now uncovered a new, unexpected role for 6beta4-integrins in maintaining nuclear stability within prostate epithelial cells.

When 6beta4-integrins are absent, the connection between the nuclear architecture and the cytokeratin-5 network is disrupted, resulting in a softening of the nucleus, changes in lamin proteins, a decrease in heterochromatin, and increased localized cell movement. Surprisingly, studies using proximity-labeling proteomics revealed that 6beta4-integrins interact with components of the nuclear pore complex (NPC) in a non-reliant manner, especially following the breakdown of hemidesmosomes. These interactions were confirmed through proximity ligation and co-immunoprecipitation methods.

The reduction of 6beta4-integrin expression was linked to enlarged nuclear pores, improper nucleocytoplasmic transport, and the accumulation of YAP1 within the nucleus. These findings were supported by a large cohort of PCa tissue samples, where decreased 6beta4-integrin levels were associated with altered nuclear shape, unfavorable clinical features, metastasis, and a poorer prognosis.

In summary, the study reveals that 6beta4-integrins play a crucial role in bridging cell-ECM adhesion, nuclear mechanics, and genome integrity, making them a vital molecular connection in prostate cancer development.