Abstract
KLF6 is ubiquitously expressed in human tissues and regulates many pathways such as differentiation, development, cellular proliferation, growth-related signal transduction, and apoptosis. We previously demonstrated that KLF6 expression is altered during liver carcinogenesis. More importantly, KLF6 invalidation results in cell cycle progression inhibition and apoptosis of liver cancer cells. On the other hand, enforced expression of KLF6 variant 2 (SV2) induces cancer cell death by apoptosis. Thus, we and others demonstrated that KLF6 and its splicing variants play a critical role in liver cancer. However, little is known on the mechanisms governing KLF6 expression in HCC. In the present work, we asked whether the 3' untranslated region (3'UTR) of the KLF6 mRNA may be responsible for regulation of KLF6 expression in HCC. We found that KLF6 mRNA stability was altered in liver-derived cell lines as compared to cervical cancer-derived cell lines and human embryonic fibroblasts. Interestingly, KLF6 mRNA was highly unstable in liver cancer-derived cell lines as compared to normal hepatocytes. We next cloned the KLF6 mRNA 3'UTR into luciferase-expressing vectors and found that gene expression and activity were strongly impaired in all liver-derived cell lines tested. In addition, we found that most the KLF6 3'UTR destabilisation activity resides between nt 1,835 and nt 2,615 of the KLF6 gene. Taken together, we provide the first steps towards better understanding of the regulation of KLF6 expression in HCC. Further work is needed to identify the factors that bind to KLF6 3'UTR to regulate its expression in liver cancer-derived cell lines.
Highlights
Krüppel-like factor 6 (KLF6, Zf9, COPEB) belongs to the family of Sp1-like/Kruppel-like factor (KLF) transcription factors that contain three highly conserved Cys2-His2 type zinc fingers located in the C-terminus and a proline and serine rich NH2 terminal activation domain [1]
KLF6 is ubiquitously expressed in human tissues and regulates many pathways such as differentiation, development, cellular proliferation, growth-related signal transduction, and apoptosis [1,4]
We asked whether KLF6 3'untranslated region (UTR) may be responsible for down regulation of KLF6 mRNA in hepatocellular carcinoma (HCC), and may contribute to cell cycle alteration of liver cancer cells
Summary
Krüppel-like factor 6 (KLF6, Zf9, COPEB) belongs to the family of Sp1-like/KLF transcription factors that contain three highly conserved Cys2-His type zinc fingers located in the C-terminus and a proline and serine rich NH2 terminal activation domain [1]. KLF6 may play a more generalized role in tumorigenenesis as a tumor suppressor gene that is inactivated in a number of human cancers by loss of heterozygosity (LOH) [5], somatic mutation, promoter hypermethylation [6] decreased expression [7] and increased alternative splicing into a dominant negative oncogenic splice variant, KLF6-SV1 [8]. Modification of transcript stability allows gene expression to be rapidly controlled without altering transcription and translation rates This mechanism has been found to be critically involved in vital processes such as cell growth and differentiation, as well as adaptation to external stimuli [19,20]. The 3'UTR serves as a binding site for numerous regulatory proteins as well as for microRNAs. In the present work, we asked whether KLF6 3'UTR may be responsible for down regulation of KLF6 mRNA in HCC, and may contribute to cell cycle alteration of liver cancer cells
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