Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells

Simple SummaryTherapeutic target is limited for patients with triple-negative breast cancer (TNBC). Through kinome-wide siRNA (709 genes) screening, DYRK1B was identified as a potential gene essential for cell proliferation and mobility of TNBC cells, particularly in DYRK1B highly expressed TNBC cells. TNBC patients with high expression of DYRK1B had poor overall survival and disease-free survival. CCDC97 and ZNF581 were positively correlated with DYRK1B expression and might be involved in DYRK1B-mediated tumor malignancy in TNBC patients, providing DYRK1B as a potential theranostic target for TNBC.Aims: The selective molecules for targeted therapy of triple-negative breast cancer (TNBC) are limited. Several kinases play pivotal roles in cancer development and malignancy. The study aims to determine if any kinases confer to malignancy of TNBC cells, which could serve as a theranostic target for TNBC. Methods: Kinome siRNA library was used to screen selective genes required for the proliferation of TNBC cells. The involvement of DYRK1B in cancer malignancy was evaluated with migration, invasion assays, and spheroid culture. The expression of DYRK1B was confirmed with quantitative PCR and immunoblotting. The clinical correlation of DYRK1B in TNBC patients was examined with tissue microarray and The Cancer Genome Atlas (TCGA) database. Results: Our results showed that silencing DYRK1B significantly suppressed cell viability in DYRK1B-high expressed TNBC cells, likely by arresting the cell cycle at the G(1) phase. Nevertheless, silencing DYRK1B had marginal effects on DYRK1B-low expressed TNBC cells. Similarly, the knockdown of DYRK1B decreased tumorsphere formation and increased cell death of the tumorsphere. Moreover, inactivation of DYRK1B by either specific inhibitor or ectopic expressing catalytic mutant of DYRK1B inhibited cell viability and metastatic characteristics, including migration and invasion. In addition, DYRK1B protein expression was elevated in tumor tissues compared to that in adjacent normal tissues of TNBC patients. Further, DYRK1B gene expression was highly correlated with CCDC97 or ZNF581 genes in TNBC cells and patients. High co-expression of DYRK1B with CCDC97 or ZNF581 was significantly associated with unfavorable overall survival and disease-free survival of TNBC patients. Conclusions: our results suggest DYRK1B might be essential for promoting tumor progression and could be a theranostic target for TNBC. Silencing or inactivation of DYRK1B might be a potential targeted therapy for TNBC.

Automated summary

The study identified DYRK1B as a potential gene essential for cell proliferation and mobility of triple-negative breast cancer (TNBC) cells, particularly in those with high DYRK1B expression, which was associated with poor overall survival. CCDC97 and ZNF581 were positively correlated with DYRK1B expression. The results suggest DYRK1B as a potential therapeutic target for TNBC patients.