Characterization of CPSF1-mediated alternative polyadenylation in cancer
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Li, Yue
issued: 2025-05-28T22:51:35Z
issued: 2025
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Metastasis, the leading cause of cancer-related death, remains a major challenge in cancer treatment. Epithelial-to-mesenchymal transition (EMT) is a well-known driver in metastasis, endowing cancer cells with enhanced migration and invasion properties. While EMT is often triggered by transcriptional reprogramming of gene expression, the contribution of post-transcriptional regulations, such as alternative polyadenylation (APA), remains largely uncharted. APA has gained attention due to its unique role in regulating 3’-untranslated regions (3’UTRs). Cleavage and polyadenylation specific factor 1 (CPSF1) is a core APA component, which facilitates recognition of the canonical poly(A) signals. However, its involvement in metastasis has yet to be thoroughly investigated. Through unbiased bioinformatics interrogation, we identified elevated CPSF1 expression across multiple distinct cancer types, which correlated with metastasis and unfavorable clinical outcomes. Functionally, CPSF1 gain-of-function studies revealed enhanced cancer cell proliferation and motility, while genetic abrogation of CPSF1 impaired cancer cell migration, invasion and EMT. CPSF1-knockout cancer cells exhibited a biased shift towards lengthened 3’UTRs in many gene transcripts through Quantitative APA (QAPA) analysis, including the key EMT regulators such as TGFBR1 and SOX9. Using ultrasound-guided sub-renal capsule xenograft models and orthotopic bladder xenograft models, we demonstrated that CPSF1-deficiency impaired tumor growth, invasion, and metastasis. Additionally, we found that CPSF1 was required to maintain CPSF complex stability by preventing ubiquitin-mediated degradation of the complex components. Collectively, our research uncovers dual function of CPSF1 in maintaining the mesenchymal features and CPSF complex stability in cancer cells. These insights position CPSF1 as a potential therapeutic target in cancer treatment.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/91224
note: CHARACTERIZATION OF CPSF1-MEDIATED ALTERNATIVE POLYADENYLATION IN CANCER by Yue Li M.Sc., Zhengzhou University, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Interdisciplinary Oncology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) May 2025 © Yue Li, 2025 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: CHARACTERIZATION OF CPSF1-MEDIATED ALTERNATIVE POLYADENYLATION IN CANCER submitted by Yue Li in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Interdisciplinary Oncology Examining Committee: Dr. Mads Daugaard, Associate Professor, Department of Urologic Sciences, UBC Supervisor Dr. Yuzhuo Wang, Professor, Department of Urologic Sciences, UBC Supervisory Committee Member Dr. Colin Collins, Professor, Department of Urologic Sciences, UBC Supervisory Committee Member Dr. Gregor Reid, Associate Professor, Department of Pediatrics, UBC University Examiner Dr. Alice Mui, Associate Professor, Department of Biochemistry and Molecular Biology, UBC University Examiner iii Abstract Metastasis, the leading cause of cancer-related death, remains a major challenge in cancer treatment. Epithelial-to-mesenchymal transition (EMT) is a well-known driver in metastasis, endowing cancer cells with enhanced migration and invasion properties. While EMT is often triggered by transcriptional reprogramming of gene expression, the contribution of post-transcriptional regulations, such as alternative polyadenylation (APA), remains largely uncharted. APA has gained attention due to its unique role in regulating 3’-untranslated regions (3’UTRs). Cleavage and polyadenylation specific factor 1 (CPSF1) is a core APA component, which facilitates recognition of the canonical poly(A) signals. However, its involvement in metastasis has yet t…
has type: Thesis/Dissertation
date issued: 2025-11
is shown at: 10.14288/1.0448969
language: eng
degree discipline: Interdisciplinary Oncology
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
contributor: Daugaard, Mads
type: Text
identifier URI: http://hdl.handle.net/2429/91224