The Transcription Regulator Krüppel-Like Factor 4 and Its Dual Roles of Oncogene in Glioblastoma and Tumor Suppressor in Neuroblastoma

Abstract

The Krüppel-like factor 4 (KLF4) gene is located on chromosome 9q31. All of the currently known 17 KLF transcription regulators that have similarity with members of the specificity protein family are distinctly characterized by the Cys₂/His₂ zinc finger motifs at their carboxyl terminals for preferential binding to the GC/GT box or the CACCC element of the gene promoter and enhancer regions. KLF4 is a transcriptional regulator of cell proliferation, differentiation, apoptosis, migration, and invasion, emphasizing its importance in diagnosis and prognosis of particular tumors. KLF4 has been implicated in tumor progression as well as in tumor suppression, depending on tumor types and contexts. Different studies so far strongly suggest that KLF4 acts as an oncogene in glioblastoma, which is the most malignant and prevalent brain tumor in human adult. It is now well established that the presence of glioblastoma stem cells (GSCs) in glioblastoma causes therapy resistance and progressive growth of the tumor. Because KLF4 is one of the key stemness factors in GSCs, it is likely that KLF4 contributes significantly to the survival of GSCs and the recurrence of glioblastoma. On the other hand, recent studies show that KLF4 can act as a tumor suppressor in human malignant neuroblastoma, which is a deadly tumor mostly in children, by inhibiting the cell cycle and activating the cell differentiation and death pathways. Our increasing understanding of the molecular mechanisms of the contrasting roles of KLF4 in glioblastoma and neuroblastoma is useful for superior diagnosis, therapy, and prognosis of these tumors of the nervous system.

Keywords: KLF4; glioblastoma; neuroblastoma; oncogene; tumor suppressor.

FIG. 1

Molecular structure of human KLF4 and its functional domains. (A) Chromosomal location of the KLF4 gene. Human chromosome 9 has the KLF4 gene at its 9q31 location. (B) Molecular organization of the KLF4 gene, which has a promoter region and five exons (dark green box/rectangles). (C) Molecular organization of KLF4 RNA transcript. Five RNA segments (dark blue) that result from the corresponding five exons contain the open reading frame for encoding the KLF4 protein, with the predicted 513 amino acids and a molecular mass of 54 kDa. (D) Distinct functional domains of the KLF4 protein. The protein sequence of human KLF4 has four distinct functional domains. The transactivation domain (green) at the amino terminal interacts with the co-activators p300/CBP. A repression domain (red) contains two lysines that can be acetylated by p300/CBP. Afterward, it contains a hexapeptide NLS (yellow). The potential PEST sequences are also shown (arrows) for their degradation by ubiquitin-proteasome pathway. Finally, the DBD at the carboxyl terminal has three consecutive ZnF motifs (ZnF1, 2, and 3) that participate in binding to the specific DNA sequence of a target gene.

FIG. 2

Roles of KLF4 as oncogene in human glioblastoma. KLF4 is highly expressed to function as an oncogene in heterogenic glioblastoma cells, especially in GSCs, in this solid tumor. Hypoxia has an important role in promoting expression of KLF4 in GSCs and other glioblastoma cells. Radiotherapy and chemotherapy fail to kill every GSC in the tumor, and only a few GSCs remaining after therapeutic treatments can regrow the tumor that can, in turn, produce more GSCs to perpetuate malignant tumor growth.

FIG. 3

Roles of KLF4 as tumor suppressor in human malignant neuroblastoma. KLF4 functions as a tumor suppressor in neuroblastoma, because no or negligible expression of KLF4 is associated with maintenance of cell proliferation, lack of terminal differentiation, and absence of apoptosis in neuroblastoma cells. Overexpression of KLF4 by an appropriate therapeutic strategy (e.g., KLF4 cDNA transfection and pharmacological treatment alone or in combination) can inhibit cell proliferation, angiogenesis, and invasion; promote terminal differentiation; and induce apoptosis to control the growth of malignant neuroblastoma.