HDAC11 and COMP Modulate Breast Cancer Cell Phenotypes and Osteoclastogenic Responses in a Co-culture Model

Background: Cartilage oligomeric matrix protein (COMP) interacts with stromal interaction molecule 1 (STIM1). Both COMP and histone deacetylase 11 (HDAC11) are highly expressed in breast cancer cells (BCC). Given the reported inhibitory effect of HDAC3 on COMP acetylation, HDAC11 may be associated with the regulation of COMP acetylation in BCC. Therefore, this study investigated the association between HDAC11, COMP, and osteoclast-related responses in breast cancer (BC) using a co-culture model, providing in vitro correlative evidence that may be relevant to the pathophysiology of bone metastasis.Methods: Bioinformatics analyses verified HDAC11/COMP expression and their correlation in invasive BC. HDAC11 and COMP expressions were manipulated in MCF-7/MDA-MB-231 cells, and then cells were co-cultured with RAW264.7 macrophages to mimic the bone microenvironment. Co-IP and in vitro acetylation assays were conducted to clarify HDAC11-COMP interaction and the association between HDAC11 knockdown and COMP acetylation levels. Functional, molecular detection and microspectrofluorometry assays were performed to assess BCC malignant phenotypes, osteoclast biological behaviors, HDAC11/COMP/STIM1 expression and intracellular Fura-2 signals.Results: HDAC11 and COMP levels were markedly upregulated and positively correlated in invasive BC (p < 0.05). HDAC11 overexpression boosted BCC viability, migration, invasion and COMP expression, while HDAC11 knockdown had the opposite effects and elevated COMP acetylation (p < 0.05). In the BCC-RAW264.7 co-culture system, HDAC11 knockdown suppressed the maintenance, survival and functional activity of differentiated osteoclast-like cells, bone resorption, STIM1 expression and Fura-2 signals in the co-cultured cell population (p < 0.001). Moreover, COMP overexpression reversed the inhibitory effects of HDAC11 knockdown on BCC malignant phenotypes, osteoclast activation, STIM1 expression and Fura-2 ratio signals (p < 0.01).Conclusion: HDAC11 knockdown is associated with increased acetylated lysine signals in COMP immunoprecipitates, along with changes in STIM1 protein abundance and Fura-2 signals in the co-culture system. Collectively, these findings reveal a correlation between HDAC11, COMP and the regulation of both BCC progression and osteoclastogenic activity, providing a basis for future in vivo studies to investigate its potential role in BC bone metastasis.