Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells
by
, ,
Chia-Che Chang
1,†, 
Chien-Chih Chiu
2,†,
Pei-Feng Liu
3,4,5,
Chih-Hsuan Wu
4,
Yen-Chiang Tseng
6,7,
Cheng-Hsin Lee
3 and
Chih-Wen Shu
8,* 1
Department of Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81300, Taiwan
2
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
3
Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
4
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
5
Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
6
Department of Surgery, Division of Thoracic Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
7
Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan
8
Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, No. 70, Lianhai Rd., Gushan Dist., Kaohsiung 80424, Taiwan
*
Author to whom correspondence should be addressed.
†
The authors equally contribute to this work.
Cancers 2021, 13(22), 5779; https://doi.org/10.3390/cancers13225779
Submission received: 30 September 2021
/
Revised: 3 November 2021
/
Accepted: 16 November 2021
/
Published: 18 November 2021
(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)
Simple Summary
Therapeutic 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.
Abstract
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.
