Research Paper Volume 12, Issue 3 pp 2030—2048
High expression of SMYD3 indicates poor survival outcome and promotes tumour progression through an IGF-1R/AKT/E2F-1 positive feedback loop in bladder cancer
- 1 Department of Urology, Peking University Third Hospital, Beijing, China
- 2 Department of Urology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Lab for Cancer Prevention and Therapy, Tianjin, China
- 3 School of Nursing, Beijing University of Chinese Medicine, Beijing, China
- 4 Department of Urology, Shandong University Qilu Hospital, Jinan, China
- 5 Department of Medicine, Bioclinicum and Centre for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden
- 6 Department of Urology, The Central Hospital of Zibo, Zibo, China
- 7 Department of Urology, Chifeng University Second Hospital, Chifeng, China
- 8 Department of Urology, The People’s Hospital of Xinjiang Uyghur Autonomous Region, Xinjiang, China
- 9 Karolinska Institute-Shandong University Collaborative Laboratory for Cancer and Stem Cell Research, Jinan, China
received: September 14, 2019 ; accepted: January 2, 2020 ; published: February 1, 2020 ;https://doi.org/10.18632/aging.102718
How to Cite
Copyright © 2020 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The AKT/mTOR pathway is critical for bladder cancer (BC) pathogenesis and is hyper-activated during BC progression. In the present study, we identified a novel positive feedback loop involving oncogenic factors histone methyltransferase SMYD3, insulin-like growth factor-1 receptor (IGF-1R), AKT, and E2F-1. SMYD3 expression was significantly up-regulated in BC tumors and positively associated with histological grade, lymph node metastasis, and shorter patient survival. Depletion of SMYD3 inhibited BC cell proliferation, colony formation, migration, invasion, and xenograft tumor growth. Mechanistically, SMYD3 inhibition led to the diminished AKT/mTOR signaling activity, thereby triggering deleterious effects on BC cells. Furthermore, SMYD3 directly activates the expression of IGF-1R, a critical activator of AKT in BC, by inducing hyper-methylation of histone H3-K4 and subsequent chromatin remodeling in the IGF-1R promoter region. On the other hand, E2F-1, a downstream factor of the AKT pathway, binds to the E2F-1 binding motifs at the SMYD3 promoter and consequently induces SMYD3 transcription and expression. Thus, SMYD3/IGF-1R/AKT/E2F-1 forms a positive feedback loop leading to the hyper-activated AKT signaling. Our findings provide not only profound insights into SMYD3-mediated oncogenic activity but also present a unique avenue for treating BC by directly disrupting this signaling circuit.