The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer
Jinbeom Heo1,2, Jinyoung Lee1, Yun Ji Nam1,2
1Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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.
Insights
Aberrant activation of embryogenesis-related pathways in bladder cancer (BC) involves TFCP2L1. We found ID2 acts as a key mediator, and its restoration suppresses BC stemness and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Aberrant activation of embryogenesis pathways in urothelial bladder cancer (BC) correlates with stemness, dedifferentiation, and metastasis.
- Overexpression and phosphorylation of transcription factor CP2-like protein-1 (TFCP2L1) by cyclin-dependent kinase-1 (CDK1) are implicated in bladder carcinogenesis.
Purpose of the Study:
- To investigate the clinical relevance and therapeutic potential of the CDK1-TFCP2L1 molecular network in bladder cancer.
- To elucidate the role of inhibitor of DNA binding-2 (ID2) as a mediator in this pathway.
Main Methods:
- Analysis of ID2 as a direct repressive target of TFCP2L1.
- Correlation of ID2 and CDK1 expression with clinical characteristics.
- Investigation of TFCP2L1's effect on ID2 promoter activity.
- Assessment of ID2 ectopic expression and apigenin treatment on BC cell behavior.
- Evaluation of combination therapy (RO-3306 and apigenin) in an orthotopic BC xenograft model.
Main Results:
- ID2 acts as a crucial mediator, directly repressed by TFCP2L1, modulating BC cell stemness and survival.
- Low ID2 and high CDK1 expression are significantly associated with unfavorable clinical characteristics.
- Ectopic ID2 expression or apigenin treatment induced apoptosis, impaired proliferation, suppressed stemness, and reduced invasion in BC cells.
- Combination treatment with a CDK1 inhibitor and apigenin significantly suppressed tumor growth in vivo.
Conclusions:
- ID2 is a direct target of the CDK1-TFCP2L1 pathway, playing a critical role in modulating BC stemness.
- The CDK1-TFCP2L1-ID2 axis represents a potential therapeutic target for bladder cancer treatment.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...