Cancer and cardiovascular diseases are two most fatal diseases causing innumerable death each year. Understanding the mechanisms underlying these diseases is critical for developing proper therapeutic approach. Kruppel-like factor 8 (KLF8) is a member of Kruppel-like family transcription factors that is overexpressed in many types of cancers. There is no report on role of KLF8 in cardiovascular diseases to date. KLF8 transcriptionally activates or represses a host of target genes to promote cancer cell proliferation, migration, invasion and epithelial to mesenchymal transition during tumor progression. Studies proposed in this thesis identified a novel posttranslational modification of KLF8 essential for its role in promoting cancer cell migration and discovered a novel function of KLF8 in cardiomyopathy. In our first study, we identified serine 48 (S48) as a novel phosphorylation site on KLF8. Pharmacological and genetic manipulations of various potential kinases further revealed ERK2 as the kinase responsible for this novel phosphorylation. Functional studies indicated that this phosphorylation is crucial for protecting KLF8 protein from degradation in the nucleus and promoting cancer cell migration. Preclinical xenograft models have indicated an important role of KLF8 for tumor progression. To investigate role of KLF8 in spontaneous tumorigenesis better recapitulating pathology in patients, we established the first Cre-regulated conditional KLF8 transgenic mouse model. Upon induction of global expression of the KLF8 transgene, spontaneous mammary and testicular tumors were formed in a small population of the mice by their mid-age, as expected considering the long latency required for tumor progression. Surprisingly, however, nearly 100% of KLF8 the mice died with a significantly enlarged heart, which did not occur to any littermate control mouse. Further characterization of the mice revealed that the global expression of the transgene caused striking systolic dysfunction leading to fatal dilated cardiomyopathy. Importantly, these similar phenotypes were reproduced in heart-specific KLF8 transgenic mice. Cardiovascular disease PCR array identified a number of genes potentially mediating KLF8-induced cardiac pathology. These results identified a previously unimagined function of KLF8 in the heart, shed new light on the mechanisms of cardiac diseases and provide novel preclinical mouse models for future translational research.
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Doctor of Philosophy (Ph.D.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Doctoral Dissertation (Open Access)
Lahiri, Satadru, "Role of Kruppel-like Factor 8 (KLF8) in Cancer and Cardiomyopathy" (2016). Electronic Theses and Dissertations, 2004-2019. 5469.