NCAPH-YAP1 interaction promotes breast cancer stemness and tumor progression

Breast cancer (BC) is the most prevalent malignant tumor in women globally. Despite improved cure rates and survival for early- to mid-stage patients, around 30% still progress to metastatic BC due to cancer stem cells (CSCs), which drive tumor recurrence, progression, metastasis, and drug resistance.

This study used bioinformatics to analyze BC datasets from gene expression omnibus (GEO), cBioportal, and The Cancer Genome Atlas (TCGA), identifying NCAPH as a gene associated with breast cancer stem cells (BCSCs) characteristics. The mRNA stemness index algorithm was used to calculate tumor stemness scores. WGCNA, Lasso regression, and Kaplan-Meier analyses validated the link between NCAPH and BC prognosis. In vitro and in vivo experiments explored NCAPH's effects on BC cells. Transcriptomic sequencing and Gene set enrichment analysis (GSEA) analysis revealed Hippo-YAP1 pathways regulated by NCAPH. Co-immunoprecipitation and immunofluorescence co-localization experiments confirmed the interaction between NCAPH and YAP1, with functional rescue experiments using the YAP1 inhibitor Verteporfin.

Results showed NCAPH was overexpressed in BC, linked to advanced tumor stages and poor prognosis. It enhanced CSCs properties, accelerated cell cycle progression, and promoted proliferation, migration, and invasion in vitro and in vivo. GSEA analysis suggested NCAPH regulates YAP1 in the Hippo signaling pathway. NCAPH promotes LATS1 and YAP1 expression, dephosphorylation, and nuclear translocation, enhancing BCSC traits and malignant phenotypes. Notably, Verteporfin reversed NCAPH-driven BCSC traits and malignant phenotypes.

This study identifies NCAPH as a novel oncogenic factor in BC. NCAPH interacts with YAP1, promoting its nuclear translocation and enhancing BCSC traits and malignancy. Critically, YAP1 inhibition reverses NCAPH-driven effects, validating the NCAPH as a promising therapeutic target.