Discovery and characterization of novel LIN28 protein inhibitors suppress stemness in neuroendocrine prostate cancer
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Ho, Chia Hao
issued: 2023-10-12T17:33:12Z
issued: 2023
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: The use of next-generation anti-androgens in the treatment of prostate cancer has led to an increase in therapy-induced neuroendocrine prostate cancer (t-NEPC). Recent studies have identified t-NEPC as a highly aggressive subtype of prostate cancer with poor survival rates. Our laboratory has recently demonstrated that the Lin28B, a core embryonic protein that suppresses the maturation process of the micro-RNA let-7, plays a crucial role in transforming adenocarcinoma prostate cancer (AdPC) into t-NEPC. Lin28B is an RNA-binding protein with two critical domains: the cold-shock domain (CSD) and the zinc-knuckle domain (ZKD). By utilizing both of CSD and ZKD domains, Lin28B protein can structurally binds to the microRNA let-7, which has been reported as a tumor suppressor and oncogene in NEPC, and inhibits its biosynthesis. Therefore, we hypothesize that blocking the interaction of CSD or ZKD with let-7 using a small molecule chemical may provide therapeutic opportunities to treat t-NEPC. In this study, we used a computer-aided drug design strategy to target Lin28B ZKD with small molecule inhibitors. We identified several inhibitors that effectively block Lin28B from binding to let-7 miRNA and restore let-7 biogenesis. Furthermore, we demonstrated that these inhibitors suppress the expression of stem-like pluripotency gene networks and neuroendocrine biomarkers. Lin28B inhibitors also reduces the expression of cancer stem cell surface markers such as CD44 and CD133. We also showed that these inhibitors suppress t-NEPC cell proliferation and clonogenic abilities. Overall, our study discovered several promising small molecules inhibitors of Lin28B that could be developed into potential drugs against NEPC.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/86124
note: DISCOVERY AND CHARACTERIZATION OF NOVEL LIN28 PROTEIN INHIBITORS SUPPRESS STEMNESS IN NEUROENDOCRINE PROSTATE CANCER by CHIA HAO HO B.Sc., University of Washington-Seattle, 2018 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2023 © CHIA HAO HO, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: DISCOVERY AND CHARACTERIZATION OF NOVEL LIN28 PROTEIN INHIBITORS SUPPRESS STEMNESS IN NEUROENDOCRINE PROSTATE CANCER Submitted by Chia Hao Ho in partial fulfillment of the requirements for the degree of Master of Science in Experimental Medicine Examining Committee: Xuesen Dong, Associate Professor, Urological Sciences, UBC Supervisor Artem Cherkasov, Professor, Urological Sciences, UBC Supervisory Committee Member Nada Lallous, Assistant Professor, Faculty of Medicine, UBC Supervisory Committee Member Colin Ross, Professor, Pharmaceutical Sciences, UBC Additional Examiner iii Abstract The use of next-generation anti-androgens in the treatment of prostate cancer has led to an increase in therapy-induced neuroendocrine prostate cancer (t-NEPC). Recent studies have identified t-NEPC as a highly aggressive subtype of prostate cancer with poor survival rates. Our laboratory has recently demonstrated that the Lin28B, a core embryonic protein that suppresses the maturation process of the micro-RNA let-7, plays a crucial role in transforming adenocarcinoma prostate cancer (AdPC) into t-NEPC. Lin28B is an RNA-binding protein with two critical domains: the cold-shock domain (CSD) and the zinc-knuckle domain (ZKD). By utilizing both of CSD and ZKD domains, Lin28B protein can structurally binds to the microRNA let-7, which has been reported as a tumor suppressor and oncogene in NEPC, and inhibits …
has type: Thesis/Dissertation
date issued: 2023-11
is shown at: 10.14288/1.0437145
language: eng
degree discipline: Experimental 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
contributor: Dong, Xuesen
type: Text
identifier URI: http://hdl.handle.net/2429/86124