Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Studies indicate that CRC is the consequence of stepwise changes (mutations) in a series of genes with important cellular functions including tumor suppressor genes (TSGs) and oncogenes. Thus, somatic or germline inactivation of TSGs such as adenomatous polyposis coli (APC), p53, and several genes involved in DNA mismatch repair; and oncogenic activation of KRAS and BRAF are thought to be crucial in the formation of CRC. Moreover, CRC is genetically unstable and this instability arises from two different pathways: chromosomal instability (CIN) and microsatellite instability (MIN). CIN, which accounts for 85% of all CRC, is thought to underlie the aneuploid state observed in CRC. The molecular mechanism that leads to CIN, however, is not well established. Our group previously identified a zinc finger-containing transcription factor called gut-enriched Kruppel-like factor (GKLF; also known as Kruppel-like factor 4 or KLF4), the expression of which is enriched in the terminally differentiated epithelial cells of the gut. KLF4 is an inhibitor of cell proliferation and does so by transcriptionally activating the gene encoding the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1). KLF4 is necessary and sufficient in mediating the inhibitory effect of the tumor suppressor, p53, on the cell cycle following DNA damage, p53-dependent induction of KLF4 leads to a block in both the G1/S and G2/M transitions in the cell cycle and prevents the entry into mitosis. Preliminary data also indicate that KLF4 is required for maintaining stability of centrosomes in cells that sustained DNA damage due to gamma irradiation. Consistent with its growth inhibitory effect, expression of KLF4 is decreased in intestinal tumors derived from the Apc(Min/+) mice, colonic adenomas from FAP patients and sporadic CRC, when compared to their respective normal adjacent mucosa. Moreover, we showed evidence of loss of heterozygosity (LOH) in the KLF4 locus in a subset of sporadic human CRC, suggesting that KLF4 itself is a tumor suppressor gene in CRC. Based on these findings, we hypothesize that KLF4 is an important tumor suppressor in CRC and is involved in maintaining genomic stability. The long-term goal of the proposed project is to understand the molecular mechanisms responsible for the formation of colorectal cancer. In the project period supported by this competitive renewal, we propose 3 Specific Aims: (1) To investigate the role of KLF4 in maintaining centrosome stability following DNA damage, (2) To determine whether KLF4 is involved in maintaining genetic stability following DNA damage, and (3) To investigate the role of KLF4 as a tumor suppressor in vivo in transgenic mice. The completion of these aims will further advance the understanding of the molecular mechanisms of colorectal cancer formation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA084197-09
Application #
7225217
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Yassin, Rihab R,
Project Start
2000-01-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
9
Fiscal Year
2007
Total Cost
$369,627
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
He, Ping; Yang, Jong Won; Yang, Vincent W et al. (2018) Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice. Gastroenterology 154:1494-1508.e13
Nandan, Mandayam O; Bialkowska, Agnieszka B; Yang, Vincent W (2018) KLF5 mediates the hyper-proliferative phenotype of the intestinal epithelium in mice with intestine-specific endogenous K-RasG12D expression. Am J Cancer Res 8:723-731
Ghaleb, Amr M; Yang, Vincent W (2017) Krüppel-like factor 4 (KLF4): What we currently know. Gene 611:27-37
Kim, Chang-Kyung; He, Ping; Bialkowska, Agnieszka B et al. (2017) SP and KLF Transcription Factors in Digestive Physiology and Diseases. Gastroenterology 152:1845-1875
Kim, Chang-Kyung; Bialkowska, Agnieszka B; Yang, Vincent W (2016) Intestinal stem cell resurgence by enterocyte precursors. Stem Cell Investig 3:49
Snider, Ashley J; Bialkowska, Agnieszka B; Ghaleb, Amr M et al. (2016) Murine Model for Colitis-Associated Cancer of the Colon. Methods Mol Biol 1438:245-54
Ruiz de Sabando, Ainara; Wang, Chao; He, Yuanjun et al. (2016) ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer. Mol Cancer Ther 15:72-83
Ghaleb, Amr M; Elkarim, Enas A; Bialkowska, Agnieszka B et al. (2016) KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis. Mol Cancer Res 14:385-96
Wang, K; Xu, R; Snider, A J et al. (2016) Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. Cell Death Dis 7:e2124
Kuruvilla, Jes G; Kim, Chang-Kyung; Ghaleb, Amr M et al. (2016) Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following ?-Radiation-Induced Gut Injury in Mice. Stem Cell Reports 6:815-824

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