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- Title
The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer.
- Authors
Heo, Jinbeom; Lee, Jinyoung; Nam, Yun Ji; Kim, YongHwan; Yun, HongDuck; Lee, Seungun; Ju, Hyein; Ryu, Chae-Min; Jeong, Seon Min; Lee, Jinwon; Lim, Jisun; Cho, Yong Mee; Jeong, Eui Man; Hong, Bumsik; Son, Jaekyoung; Shin, Dong-Myung
- Abstract
Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells. Bladder cancer: Slowing tumor growth by suppressing the suppressor Combination therapy with apigenin, a powerful antioxidant found in plants such as parsley and camomile, and a drug that inhibits the cell cycle protein CDK1 shows promise for developing therapies for bladder cancer (BC). Switching on genes usually activated in stem cells can cause cancer, including BC. Although CDK1 was known to activate one of these genes in BC cells, no way to suppress the activation had been identified. Jinbeom Heo at University of Ulsan College of Medicine, South Korea, and coworkers investigated CDK1's role in BC. They found that the transcription factor activated by CDK1 suppressed a protein, ID2, that suppressed stem cell-like characteristics. Simultaneously suppressing CDK1 and boosting ID2 with apigenin strongly repressed tumor growth in a mouse model. These results help point the way to developing new treatment options for BC patients.
- Publication
Experimental & Molecular Medicine EMM, 2022, Vol 54, Issue 6, p801
- ISSN
1226-3613
- Publication type
Article
- DOI
10.1038/s12276-022-00786-0