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Published on: September 30, 2016
KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling
Yongzheng Ma1, Lin Wu1, Xuewu Liu2
1The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
Abstract:
Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor, which was confirmed as a tumor suppressor gene in colorectal cancers. KLF4 inhibits colorectal cancer cells proliferation through upregulating p21WAF1/Cip1 and downregulating cyclin D1. We firstly reported that N-Myc downstream regulated gene 2 (NDRG2) was a novel tumor suppressor gene in multiple cancers, such as glioma, breast cancer and colorectal cancer. Herein, we provide novel evidence that KLF4 can transcriptionally activate NDRG2 by binding with NDRG2 promoter. With MTT assay, EdU staining, colony formation assay and xenograft mouse model, we confirmed that KLF4 inhibited colorectal cancer cell proliferation and tumorigenesis dependent on NDRG2. Finally, with tissue array analysis, we found a positive correlation of combined detection of KLF4/NDRG2 co-expression with TNM grades and differentiation levels of colorectal cancer. Lower expression of KLF4 and NDRG2 in colorectal cancer patients was correlated with poor overall survival. Thus, KLF4 inhibited the proliferation of colorectal cancer cells dependent on NDRG2 signaling, which provides a novel strategy for therapy and early diagnosis of colorectal cancer.
Insights
Krüppel-like factor 4 (KLF4) suppresses colorectal cancer by activating N-Myc downstream regulated gene 2 (NDRG2). This KLF4-NDRG2 pathway inhibits tumor growth and correlates with patient survival, offering new diagnostic and therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Krüppel-like factor 4 (KLF4) is a known tumor suppressor in colorectal cancer, inhibiting proliferation via p21WAF1/Cip1 and cyclin D1.
- N-Myc downstream regulated gene 2 (NDRG2) has emerged as a novel tumor suppressor across multiple cancer types, including colorectal cancer.
Purpose of the Study:
- To investigate the regulatory relationship between KLF4 and NDRG2 in colorectal cancer.
- To elucidate the role of the KLF4-NDRG2 axis in colorectal cancer proliferation and tumorigenesis.
- To assess the clinical significance of KLF4 and NDRG2 co-expression in colorectal cancer patients.
Main Methods:
- In vitro assays (MTT, EdU staining, colony formation) to assess cell proliferation.
- Xenograft mouse models to evaluate tumor growth inhibition.
- Tissue array analysis to correlate KLF4/NDRG2 expression with clinical parameters and patient survival.
Main Results:
- KLF4 directly activates NDRG2 transcription by binding to its promoter.
- KLF4 suppresses colorectal cancer cell proliferation and tumorigenesis in an NDRG2-dependent manner.
- Combined KLF4/NDRG2 expression positively correlates with TNM grades and differentiation levels.
- Lower KLF4 and NDRG2 expression is associated with poor overall survival in colorectal cancer patients.
Conclusions:
- KLF4 acts as a tumor suppressor in colorectal cancer by transcriptionally activating NDRG2.
- The KLF4-NDRG2 signaling pathway is crucial for inhibiting colorectal cancer cell proliferation and tumorigenesis.
- KLF4 and NDRG2 represent potential biomarkers for early diagnosis and therapeutic targets in colorectal cancer.
