Wnt signaling is overactive in a majority of colon cancers, and its oncogenic actions depend on LEF/TCF transcription factor-dependent misregulation of target genes.
eBook Title: Expression and Actions of LEF/TCFS in Colon Cancer
Author:Kira Tricia Pate
Published on 2012 by
Wnt signaling is overactive in a majority of colon cancers, and its oncogenic actions depend on LEF/TCF transcription factor-dependent misregulation of target genes. Dominant negative (dn) LEF/TCF proteins, products of alternative promoter usage, are co-expressed with full-length (FL) LEF/TCFs in normal, untransformed tissue to moderate Wnt signaling and suppress the development of an oncogenic gene program. However, in cancer, dnLEF/TCFs are not expressed and full-length isoforms act unopposed, leading to overactive, inappropriate expression of target genes. This dissertation focuses on two major aims: i) to define the mechanisms by which this aberrant LEF/TCF expression pattern is established in colon cancer, and ii) to characterize the molecular and functional consequences of re-expressed dnLEF/TCFs. We address the first aim through a molecular characterization of the LEF/TCF promoters. Consistent with previous studies for LEF-1, we show that the promoters for FL LEF/TCFs are direct targets of the Wnt pathway. We also define basic regulation of the internal, dnLEF-1 promoter as being actively silenced through the actions of a distal negative regulatory element and a Yin Yang 1 (YY1) transcription factor binding site in the core promoter. To address the second aim, we utilize ectopic re-expression of dnLEF/TCF proteins to block endogenous Wnt signaling in colon cancer cells. Biochemical analysis and Fluorescence Lifetime Imaging Microscopy (FLIM) of living cultures and tumors show that interference with Wnt signaling skews cellular metabolism from Warburg-type glycolysis, to more of an oxidative phosphorylation mode of metabolism. This switch does not affect proliferation in vitro but has drastic consequences in vivo, resulting in small, poorly vascularized tumors. We identify a novel Wnt target gene, pyruvate dehydrogenase kinase (PDK1), and show that re-introduction rescues Warburg metabolism in vitro and in vivo. Surprisingly, PDK1 also rescues vessel density. We thus have revealed a novel function of Wnt signaling and its key target PDK1, in promoting a cell-intrinsic program of glycolysis, and we propose that this metabolic program directs a cell-extrinsic program of angiogenesis in the tumor microenvironment.
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Kira Tricia Pate
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- Expression and Actions of LEF/TCFS in Colon Cancer published by since 2012 with ISBNs. The book ISBN 13 Code is 9781267819222 and ISBN 10 Code is 1267819227
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