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Functional Investigations of Capicua (CIC) and ATAXIN-1-Like (ATXN1L) in cancer.

University of British Columbia

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 role in the post-translational regulation of CIC. The results of these studies illuminate our understanding and the intricacy of mechanisms which regulate normal CIC function in cancer; and further supports the role of CIC as a potent tumour suppressor in a multitude of cancer types.

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2020-12-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76913

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/