HSPA8 globally modulates transcriptome profile and PI3K/AKT signaling pathway to facilitate malignant progression phenotypes of triple-negative breast cancer

Abstract

Objective Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer. HSPA8 is a chaperone protein involved in the proper folding or degradation of many proteins that are implicated in various types of cancers, while its role in TNBC remains unclear. Methods In this study, we extensively explored the cellular function and molecular targets of HSPA8 in TNBC cells by performing small interfering RNA (siRNA)-mediated knockdown, followed by cytological assays and transcriptome sequencing (RNA-seq). Results The results of HSPA8 expression levels across distinct breast cancer subtypes indicated that TNBC exhibits higher HSPA8 expression. Then, cytological experiments demonstrated that knockdown of HSPA8 significantly inhibited TNBC cell proliferation, invasion and migration, and induced apoptosis. Mechanistically, RNA-seq showed that HSPA8 globally regulates gene expression and alternative splicing (AS), particularly modulating expression of genes in PI3K/AKT signaling pathway, and AS of genes in protein phosphorylation. Finally, we experimentally confirmed that knockdown of HSPA8 significantly suppressed the activation of the PI3K/AKT axis and AKT phosphorylation in TNBC cells. Conclusions Our findings highlight an important pro-oncogenic role of HSPA8 in TNBC progression, mediated in part through transcriptomic remodeling and activation of the PI3K/AKT signaling pathway. These results may inform the development of novel targets and strategies for future targeted therapy in TNBC.