Functional inactivation of the KLF6 tumor suppressor gene by loss of heterozygosity and increased alternative splicing in glioblastoma

Olga Camacho-Vanegas, Goutham Narla, Miriam S. Teixeira, Analisa DiFeo, Anjan Misra, Gobind Singh, Andrew M. Chan, Scott L. Friedman, Burt G. Feuerstein, John A. Martignetti

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Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor and possesses a high incidence of 10p loss. The KLF6 (Kruppel-like transcription factor) tumor suppressor gene on 10p15 is inactivated by loss of heterozygosity (LOH) and/or somatic mutation in a number of human cancers and forced expression of KLF6 in GBM lines inhibits their growth and transformation. In addition, increased expression of its alternatively spliced, cytoplasmic isoform KLF6-SV1 has now been shown to play a role in cancer pathogenesis. On the basis of these findings we examined the role of KLF6 and KLF6-SV1 in the development and progression of GBM. LOH analysis of 17 primary GBM patient samples using KLF6-specific microsatellite markers revealed that 88.2% (15/17) had LOH of the KLF6 locus. Interestingly, no KLF6 somatic mutations were identified. RNA analysis revealed concomitant decreases in all primary GBM tumors (n = 11) by ∼80% in KLF6 expression (p < 0.001) coupled with increased KLF6-SV1 expression (p < 0.001) when compared to normal astrocytes. To determine the biological relevance of these findings, we examined the effect of KLF6 expression and KLF6-SV1 knockdown in A235 and CRL2020 cell lines. Reconstitution of KLF6 decreased cell proliferation by almost 50%, whereas targeted KLF6 reduction increased cell proliferation 2.5-4.5 fold. Conversely, targeted KLF6-SV1 reduction decreased cell proliferation by 50%. Taken together, our findings demonstrate that KLF6 allelic imbalance and decreased KLF6 and increased KLF6-SV1 expression are common findings in primary GBM tumors, and these changes have antagonistic effects on the regulation of cellular proliferation in GBM cell lines.

Original languageEnglish (US)
Pages (from-to)1390-1395
Number of pages6
JournalInternational Journal of Cancer
Volume121
Issue number6
DOIs
StatePublished - Sep 15 2007

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Keywords

  • GBM
  • KLF6
  • KLF6-SV1
  • LOH

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Camacho-Vanegas, O., Narla, G., Teixeira, M. S., DiFeo, A., Misra, A., Singh, G., Chan, A. M., Friedman, S. L., Feuerstein, B. G., & Martignetti, J. A. (2007). Functional inactivation of the KLF6 tumor suppressor gene by loss of heterozygosity and increased alternative splicing in glioblastoma. International Journal of Cancer, 121(6), 1390-1395. https://doi.org/10.1002/ijc.22809