AURKB and PI3K/AKT/mTOR pathways converge to regulate TERT expression

Grace Lim; Althea Bastian; Saskia Fung; Farhana Mollah; Minh H Nguyen; Adwoa A Sey; Marthe Cheade; Rozelle Harvie; Nisha R Singh; Sergey Kurdyukov; Kristie-Ann Dickson; Eugene H Y Choi; Ailise C Seery; Matti L Gild; Deborah J Marsh; Hilda A Pickett; Roger R Reddel; Martyn Bullock; Roderick J Clifton-Bligh

doi:10.1016/j.isci.2025.113194

AURKB and PI3K/AKT/mTOR pathways converge to regulate TERT expression

iScience. 2025 Jul 24;28(8):113194. doi: 10.1016/j.isci.2025.113194. eCollection 2025 Aug 15.

Authors

Grace Lim¹, Althea Bastian^{1

2}, Saskia Fung^{1

3}, Farhana Mollah¹, Minh H Nguyen¹, Adwoa A Sey¹, Marthe Cheade¹, Rozelle Harvie¹, Nisha R Singh⁴, Sergey Kurdyukov⁵, Kristie-Ann Dickson², Eugene H Y Choi⁶, Ailise C Seery¹, Matti L Gild^{1

7}, Deborah J Marsh², Hilda A Pickett⁸, Roger R Reddel⁶, Martyn Bullock^{1

2}, Roderick J Clifton-Bligh^{1

7}

Affiliations

¹ Cancer Genetics Laboratory, Kolling Institute, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney & Northern Sydney Local Health District, St Leonards, NSW, Australia.
² Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia.
³ Wollongong Hospital, Wollongong, NSW, Australia.
⁴ NSW Health Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia.
⁵ Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia.
⁶ Cancer Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.
⁷ Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW, Australia.
⁸ Telomere Length Regulation Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.

Abstract

Telomere length maintenance, critical for cancer progression, can be driven by TERT promoter mutations (TERTp ^MUT ), which are markers of poor prognosis across multiple cancers. Their tumor-specificity also makes them attractive chemotherapeutic targets. Here, we identified previously uncharacterized pathways regulating TERTp ^MUT activity by inserting a luciferase reporter downstream of TERTp ^MUT in SW1736 anaplastic thyroid cancer cells via CRISPR-Cas9, generating SW1736^TERT/LUC, and screening a 218-kinase inhibitor library. Beyond MAPK regulation, we found co-regulatory roles for PI3K/AKT/mTOR1 signaling and the cell cycle via Aurora kinase B (AURKB). Further analyses using quantitative PCR, immunoprecipitation (IP), and chromatin IP in thyroid cell models revealed that although both TERTp ^MUT and wild-type promoters are governed by these pathways, distinct factors mediate each mechanism. Specifically, AURKB, via REST, is recruited to TERTp ^MUT by TRIM28. These findings highlight TRIM28 as a promising therapeutic target for TERTp ^MUT -driven thyroid cancers.

Keywords: Cell biology; Molecular biology; Oncology.