This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ito, G. Articles by Sekido, Y. Search for Related Content PubMed PubMed Citation Articles by Ito, G. Articles by Sekido, Y.

Krüppel-Like Factor 6 Is Frequently Down-Regulated and Induces Apoptosis in Non-Small Cell Lung Cancer Cells

Departments of ¹ Clinical Preventive Medicine, ² Respiratory Medicine, and ³ Thoracic Surgery, Nagoya University School of Medicine, Nagoya, Japan

Krüppel-like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcriptional factor, which has been suggested to be a candidate tumor suppressor gene in prostate cancer and astrocytic glioma. Because KLF6 is located at chromosome 10p15, where non-small cell lung cancers (NSCLCs) also exhibit frequent allelic loss, we hypothesized that the inactivation of KLF6 is also involved in the development of NSCLC. To determine this, we performed mutational analysis for 105 NSCLCs, including 9 cell lines and 96 primary tumors, and Northern blot analysis for 74 NSCLCs, including the 9 cell lines and 65 primary tumors. Although somatic mutations were not detected in the coding sequence of KLF6, expression of KLF6 mRNA was down-regulated in the 9 cell lines and in 55 (85%) of the 65 primary tumors compared with normal lung tissue. Treatment of two cell lines expressing KLF6 at low levels with 5-azacytidine did not induce KLF6 expression, suggesting that KLF6 down-regulation is not due to promoter hypermethylation. We also performed loss of heterozygosity (LOH) analysis using the laser capture microdissection technique, and found that 21 of 62 (34%) informative samples had LOH in the KLF6 gene locus. Comparing the LOH status with mRNA expression of KLF6, we found that 14 of the 14 (100%) samples with LOH showed KLF6 down-regulation, and that even 23 of 31 (74%) samples without LOH also showed this down-regulation. We also studied the expression of the WAF1 gene, a possible downstream gene of KLF6, and detected simultaneous down-regulation of WAF1 and KLF6 mRNA in 6 of 9 (67%) cell lines and 48 of the 55 (87%) primary tumors, although there was not a significant association between loss of KLF6 and WAF1 expression. Furthermore, colony formation assay of two NSCLC cell lines (NCI-H1299 and NCI-H2009) induced a markedly reduced colony formation by KLF6 transfection, and Annexin V staining and terminal deoxynucleotidyl transferase-mediated nick end labeling assays revealed that KLF6 induced apoptosis. Our present studies demonstrated that KLF6 is frequently down-regulated in NSCLC and suppresses tumor growth via induction of apoptosis in NSCLC, which may suggest that KLF6 is a tumor suppressor for NSCLC.

This article has been cited by other articles:

				I. Bentov, G. Narla, H. Schayek, K. Akita, S. R. Plymate, D. LeRoith, S. L. Friedman, and H. Werner Insulin-Like Growth Factor-I Regulates Kruppel-Like Factor-6 Gene Expression in a p53-Dependent Manner Endocrinology, April 1, 2008; 149(4): 1890 - 1897. [Abstract] [Full Text] [PDF]

				A. DiFeo, L. Feld, E. Rodriguez, C. Wang, D. G. Beer, J. A. Martignetti, and G. Narla A Functional Role for KLF6-SV1 in Lung Adenocarcinoma Prognosis and Chemotherapy Response Cancer Res., February 15, 2008; 68(4): 965 - 970. [Abstract] [Full Text] [PDF]

				J. Shi, Z. Hu, K. Pabon, and K. W. Scotto Caffeine Regulates Alternative Splicing in a Subset of Cancer-Associated Genes: a Role for SC35 Mol. Cell. Biol., January 15, 2008; 28(2): 883 - 895. [Abstract] [Full Text] [PDF]

				S. Mahabir, M. R. Forman, S. L. Barerra, Y. Q. Dong, M. R. Spitz, and Q. Wei Joint Effects of Dietary Trace Metals and DNA Repair Capacity in Lung Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2756 - 2762. [Abstract] [Full Text] [PDF]

				A. DiFeo, G. Narla, J. Hirshfeld, O. Camacho-Vanegas, J. Narla, S. L. Rose, T. Kalir, S. Yao, A. Levine, M. J. Birrer, et al. Roles of KLF6 and KLF6-SV1 in Ovarian Cancer Progression and Intraperitoneal Dissemination. Clin. Cancer Res., June 15, 2006; 12(12): 3730 - 3739. [Abstract] [Full Text] [PDF]

				N. Zhu, L. Gu, H. W. Findley, C. Chen, J.-T. Dong, L. Yang, and M. Zhou KLF5 Interacts with p53 in Regulating Survivin Expression in Acute Lymphoblastic Leukemia J. Biol. Chem., May 26, 2006; 281(21): 14711 - 14718. [Abstract] [Full Text] [PDF]

				N. Matsumoto, A. Kubo, H. Liu, K. Akita, F. Laub, F. Ramirez, G. Keller, and S. L. Friedman Developmental regulation of yolk sac hematopoiesis by Kruppel-like factor 6 Blood, February 15, 2006; 107(4): 1357 - 1365. [Abstract] [Full Text] [PDF]

				D. Li, S. Yea, G. Dolios, J. A. Martignetti, G. Narla, R. Wang, M. J. Walsh, and S. L. Friedman Regulation of Kruppel-like Factor 6 Tumor Suppressor Activity by Acetylation Cancer Res., October 15, 2005; 65(20): 9216 - 9225. [Abstract] [Full Text] [PDF]