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Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer
Chia-Che Chang1, Chien-Chih Chiu2, Pei-Feng Liu3,4,5
1Department of Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81300, Taiwan.
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 G1 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.
Insights
DYRK1B kinase is crucial for triple-negative breast cancer (TNBC) progression. Targeting DYRK1B shows potential as a new therapy for TNBC, improving patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted therapy options for triple-negative breast cancer (TNBC) are limited.
- Kinases are critical regulators of cancer cell development and malignancy.
- Identifying novel targets is essential for advancing TNBC treatment.
Purpose of the Study:
- To screen for kinases involved in TNBC malignancy.
- To evaluate DYRK1B as a potential theranostic target for TNBC.
Main Methods:
- Utilized a kinome siRNA library to screen TNBC proliferation genes.
- Assessed DYRK1B's role using migration, invasion, and spheroid assays.
- Confirmed DYRK1B expression and clinical relevance via qPCR, immunoblotting, tissue microarrays, and TCGA data.
Main Results:
- Silencing DYRK1B significantly reduced viability and tumorsphere formation in high-DYRK1B TNBC cells, causing G1 cell cycle arrest.
- DYRK1B inhibition decreased cell viability and metastatic characteristics (migration, invasion).
- Elevated DYRK1B expression in tumors correlated with poor survival outcomes, particularly when co-expressed with CCDC97 or ZNF581.
Conclusions:
- DYRK1B is essential for TNBC tumor progression.
- DYRK1B represents a promising theranostic target for TNBC.
- Targeting DYRK1B through silencing or inhibition may offer a new therapeutic strategy for TNBC.
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