Functional Investigations of Capicua (CIC) and ATAXIN-1-Like (ATXN1L) in cancer.
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Wong, Derek
issued: 2020-12-24T20:59:01Z
issued: 2020
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Mutations in the Capicua (CIC) gene, located on chromosome 19q, were first identified in up to 70% of 1p19q-codeleted, IDH-mutated Oligodendrogliomas (ODGs), a subtype of diffuse low grade glioma (DLGG). Since then, several studies have highlighted that loss or dysregulation of CIC is associated with tumour progression, worse prognosis, and treatment resistance in multiple cancer types. One CIC binding partner, Ataxin-1-Like (ATXN1L), has been implicated as an important regulator of CIC function in murine development, but little is known in the context of cancer. In this thesis, we characterize the functional interaction between CIC and ATXN1L and their relationship in regulating pathways involved in tumourigenesis. The function of ATXN1L in relation to CIC was investigated by assessing and comparing the transcriptomic consequences of ATXN1L knockout (KO) and CIC KO using isogenic cell lines. Loss of either CIC or ATXN1L led to concordant dysregulation of gene sets in each context which converged upon several pathways involved in differentiation and activation of the mitogen activated protein kinase (MAPK) pathway as a result of decreased CIC-DNA binding. Further analysis of cancers harboring deletions in CIC and ATXN1L, namely, stomach adenocarcinoma, prostate adenocarcinoma, and astrocytoma, resulted in convergent dysregulation of several pathways involved in cell proliferation and growth. In addition to decreased CIC-DNA binding, loss of ATXN1L resulted in increased CIC protein instability as a result of proteasomal degradation which was found to be independent of ERK activity, the canonical CIC degradation pathway. Instead, loss of ATXN1L was found to promote CIC instability through ubiquitination by the E3-ligase TRIM25, a novel CIC interactor. Transcriptomic analyses of breast carcinomas with TRIM25 amplification and liver hepatocellular carcinomas with high TRIM25 expression revealed dysregulation of genes and pathways reminiscent of CIC loss, supporting its …
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/76913
note: Functional Investigations of Capicua (CIC) and ATAXIN-1-Like (ATXN1L) in cancer. by Derek Wong A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2020 ©Derek Wong, 2020ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Functional Investigations of Capicua (CIC) and ATAXIN-1-Like (ATXN1L) in cancer. submitted by Derek Wong in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pathology and Laboratory Medicine Examining Committee: Dr. Stephen Yip MD, PhD, FRCPC, Pathology and Laboratory Medicine Supervisor Dr. David Huntsman, MD, FRCPC, FCCMG, Pathology and Laboratory Medicine Co-supervisor Dr. Poul Sorensen, MD, PhD,FRCPC, Pathology and Laboratory Medicine University Examiner Dr. Amina Zoubeidi, PhD, Urologic Sciences University Examiner Additional Supervisory Committee Members: Dr. Marcel Bally, PhD, Experimental Therapeutics Supervisory Committee Member Dr. Marco Marra, PhD, FRS(C), FCAHS, OBC, Medical Genetics Supervisory Committee Member iii Abstract Mutations in the Capicua (CIC) gene, located on chromosome 19q, were first identified in up to 70% of 1p19q-codeleted, IDH-mutated Oligodendrogliomas (ODGs), a subtype of diffuse low grade glioma (DLGG). Since then, several studies have highlighted that loss or dysregulation of CIC is associated with tumour progression, worse prognosis, and treatment resistance in multiple cancer types. One CIC binding partner, Ataxin-1-Like (ATXN1L), has been implicated as an important regulator of CIC function in murine development, but little is known in the context of cancer. In this thesis, we characterize the functional interaction between CIC and ATXN1L and their relationship in regulating pat…
has type: Thesis/Dissertation
date issued: 2021-05
is shown at: 10.14288/1.0395396
language: eng
degree discipline: Pathology and Laboratory Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/76913