The Resource Characterization of Esrrb function in metastatic prostate cancer cells and transcriptional regulation of hedgehog-signaling pathway target genes, by Yuan Lu

Characterization of Esrrb function in metastatic prostate cancer cells and transcriptional regulation of hedgehog-signaling pathway target genes, by Yuan Lu

Label
Characterization of Esrrb function in metastatic prostate cancer cells and transcriptional regulation of hedgehog-signaling pathway target genes
Title
Characterization of Esrrb function in metastatic prostate cancer cells and transcriptional regulation of hedgehog-signaling pathway target genes
Statement of responsibility
by Yuan Lu
Title variation
Characterization of Estrogen Receptor Related Beta function in metastatic prostate cancer cells and transcriptional regulation of hedgehog-signaling pathway target genes
Creator
Contributor
Author
Thesis advisor
Subject
Genre
Language
eng
Summary
Orphan nuclear receptor Estrogen Receptor Related Receptor [Beta] (Esrrb) is a transcription factor. It is intensively studied for its function in embryo development and induced pluripotent stem cell induction. Although it was also shown to be important in cancer, little is known about its function in cancer cells and cancer relevant pathways. In this dissertation, we focus on Esrrb's transcription targets discovery in prostate cancer cells, as well as its function in regulating Hedgehog (Hh)-signaling and Akt signaling pathways. Here we report our discovery of Esrrb-targeted genes in metastatic prostate cancer cells and distinguish a group of target genes responsive to the Esrrb selective ligand DY131. Although there is argument about whether the intrinsic transactivation activity is ligand dependent, we found Esrrb has both ligand-dependent and ligand-independent transactivation activities. We also characterized a collection of Esrrb- (67 genes) and Esrrb-dependent DY131- responsive (1161 genes) genes and defined a group of genes for which DY131 serves as an agonist or antagonist through Esrrb. These results expand the understanding of the transcription regulatory function of Esrrb and provide a handful of reference markers regarding Esrrb activity. To understand the mechanism of Esrrb-driven gene expression alteration, we built a bioinformatics pipeline that predicts transcription factor binding and target genes using an in-house bioinformatics tool. The comparison between the DY131-activated Esrrb-driven gene regulation network and the ligand independent Esrrb gene regulation network infers that DY131 expands the effects of Esrrb. Gene set enrichment analysis shows Esrrb target genes are related to cell proliferation, regulation of apoptosis and transcription regulation, supporting its role as a transcription factor and its known function in inhibiting prostate cancer cells proliferation. Esrrb, as well as the Hh-signaling pathway, are known for their functions in inducing pluripotent stem cells and their important role in tumorigenesis. We hypothesize that the Esrrb and Hh-signaling pathways functionally overlap in gene expression regulation, and that Esrrb can regulate Hh-signaling activity. Using RNA-Seq in an Esrrb-expressing Hh-responsive cell line and an in-house innovative computational decision tree gene-sorting tool, we sorted Hh-signaling and Esrrb-responsive genes in different groups based on their mRNA concentration in different conditions. In addition to a full list of Hh-signaling and Esrrb target genes, we found 109 Hh-signaling differentially responsive genes, which respond to Hh ligand differently with or without Esrrb expression. The presence of these genes clearly show that Esrrb is capable of regulating Hh-signaling pathway activity. In addition, co-treatment of DY131 with Hh ligand completely removed Hh-ligand's effect on all tested Hh-target genes without Esrrb expression, supporting the reported direct SMO inhibitory role of DY131. However, when Esrrb is expressed, DY131 treatment lost the anti-Hh effect on a group of genes including Sfrp2, Prl2c3, Hp, Hoxd8, Dpt, Pdcd4, Smoc2, Hsd11b1 and Ogn, indicating DY131 also regulates these genes in an Esrrb-dependent manner and Esrrb ligand can be used to alter these genes' response to Hh-signaling activation. Since Akt activity was reported to be responsive to Hh-activated Smoothened (SMO), and Akt over-activation was reported to be one of the mechanisms of anti-Hh treatment Vismodegib resistance, with the result that DY131 is an SMO inhibitor, we hypothesized DY131 can inhibit SMO-driven Akt activity. We found Akt phosphorylation (pAkt) is stimulated by Hh treatment, and the addition of DY131 can inhibit both basal level and Hh-stimulated pAkt. A similar pAkt inhibition is also observed in DU145 cells, which are SMO inactive and Esrrb null, indicating the pAkt inhibition is not SMO or Esrrb dependent. Interestingly, although DY131 is likely to inhibit pAkt by binding to Esrrb, Esrrb itself also has the ability to inhibit pAkt in DU145 cells. These results strongly indicate either DY131 or Esrrb can be used to prevent Vismodegib resistance. Overall, our comprehensive analysis of Esrrb-regulated gene expression shows that Esrrb is a significant factor regulating cellular proliferation and apoptosis. Its activity in regulating Hh-signaling target gene expression and Akt inhibitory effect indicates Esrrb can potentially serve as a therapeutic target in cancer treatment
Cataloging source
MUU
http://library.link/vocab/creatorDate
1986-
http://library.link/vocab/creatorName
Lu, Yuan
Degree
Ph. D.
Dissertation note
Thesis
Dissertation year
2014.
Government publication
government publication of a state province territory dependency etc
Granting institution
University of Missouri--Columbia
Index
no index present
Literary form
non fiction
Nature of contents
  • dictionaries
  • bibliography
  • theses
http://library.link/vocab/relatedWorkOrContributorDate
1954-
http://library.link/vocab/relatedWorkOrContributorName
Lubahn, Dennis B.
http://library.link/vocab/subjectName
  • Nuclear receptors (Biochemistry)
  • Cellular signal transduction
  • Transcription factors
  • Prostate
Label
Characterization of Esrrb function in metastatic prostate cancer cells and transcriptional regulation of hedgehog-signaling pathway target genes, by Yuan Lu
Instantiates
Publication
Note
  • "A Dissertation Presented to The Faculty of the Graduate School University of Missouri-Columbia In Partial Fulfillment Of the Requirement for the Degree Doctor of Philosophy."
  • Dissertation supervisor: Dr. Dennis B. Lubahn
  • Includes vita
Bibliography note
Includes bibliographical references (pages 144-160)
Carrier category
online resource
Carrier category code
  • cr
Carrier MARC source
rdacarrier
Content category
text
Content type code
  • txt
Content type MARC source
rdacontent
Control code
973494747
Extent
1 online resource (xiv, 161 pages)
Form of item
online
Media category
computer
Media MARC source
rdamedia
Media type code
  • c
Other physical details
illustrations (some color)
Specific material designation
remote
System control number
(OCoLC)973494747
Label
Characterization of Esrrb function in metastatic prostate cancer cells and transcriptional regulation of hedgehog-signaling pathway target genes, by Yuan Lu
Publication
Note
  • "A Dissertation Presented to The Faculty of the Graduate School University of Missouri-Columbia In Partial Fulfillment Of the Requirement for the Degree Doctor of Philosophy."
  • Dissertation supervisor: Dr. Dennis B. Lubahn
  • Includes vita
Bibliography note
Includes bibliographical references (pages 144-160)
Carrier category
online resource
Carrier category code
  • cr
Carrier MARC source
rdacarrier
Content category
text
Content type code
  • txt
Content type MARC source
rdacontent
Control code
973494747
Extent
1 online resource (xiv, 161 pages)
Form of item
online
Media category
computer
Media MARC source
rdamedia
Media type code
  • c
Other physical details
illustrations (some color)
Specific material designation
remote
System control number
(OCoLC)973494747

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