FASN Negatively Regulates NF-kB/P65 Expression in Breast Cancer Cells by Disrupting Its Stability

dc.contributor.advisorLu, Tao
dc.contributor.advisorZhang, Jian-Ting
dc.contributor.authorBarlow, Lincoln James
dc.contributor.otherFehrenbacher, Jill
dc.contributor.otherHerbert, Brittney-Shea
dc.contributor.otherSafa, Ahmad
dc.date.accessioned2020-03-11T17:49:57Z
dc.date.available2020-03-11T17:49:57Z
dc.date.issued2020-02
dc.degree.date2020en_US
dc.degree.discipline
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractThe overexpression of the multi-domain enzyme fatty acid synthase (FASN) has long been associated with poor clinical prognosis and treatment outcome in various cancers. Previous research in the Zhang lab has determined a role for FASN in mediating increases in non-homologous end-joining (NHEJ) DNA double-strand break repair activity allowing for increased cancer cell survival, and this mechanism was found to involve inhibition of NF-kB/p65. The mechanism responsible for the regulation of NF-kB/p65 by FASN in cancer cells, however, remains unknown. To this end, I was able to determine that FASN negatively regulates both the expression and activity of NF-kB/p65 in breast cancer cells, and that this effect was likely mediated by the 16-carbon saturated fatty acid palmitate, the end product of FASN catalytic activity. Specifically, FASN was found to negatively regulate p65 expression by disrupting its protein stability as a result of an increase in poly-ubiquitination of p65 protein and subsequent proteasomal degradation. Further, I found that the phosphorylation site Thr254 of p65 is involved in the regulation of p65 protein stability by FASN, in that mutation of this residue resulted in a disruption in p65 stability. Finally, I was able to determine that FASN likely inhibits the ability of the peptidyl-prolyl cis/trans isomerase Pin1 to assist in maintaining p65 stability, in that both siRNA knockdown and pharmacological inhibition of Pin1 resulted in a reduction of p65 expression in FASN shRNA knockdown cells. The determination of this signaling mechanism serves to expand our understanding of the role of FASN in breast cancer cells and has the potential to assist in uncovering more effective ways to target the oncogenic FASN pathway to kill breast tumor cells and to overcome resistance to drug treatment.en_US
dc.identifier.urihttps://hdl.handle.net/1805/22284
dc.identifier.urihttp://dx.doi.org/10.7912/C2/339
dc.language.isoen_USen_US
dc.subjectbreast canceren_US
dc.subjectDNA repairen_US
dc.subjectFASNen_US
dc.subjectNF-kBen_US
dc.subjectpalmitateen_US
dc.subjectprotein stabilityen_US
dc.titleFASN Negatively Regulates NF-kB/P65 Expression in Breast Cancer Cells by Disrupting Its Stabilityen_US
dc.typeThesis
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