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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
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041758/ https://www.ncbi.nlm.nih.gov/pubmed/32007952 http://dx.doi.org/10.18632/aging.102718 |
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author | Wang, Guoliang Huang, Yi Yang, Feilong Tian, Xiaojun Wang, Kun Liu, Li Fan, Yidong Li, Xiaofeng Li, Luchao Shi, Benkang Hao, Yichang Xia, Chuanyou Nie, Qingsheng Xin, Yue Shi, Zhenfeng Ma, Lulin Xu, Dawei Liu, Cheng |
author_facet | Wang, Guoliang Huang, Yi Yang, Feilong Tian, Xiaojun Wang, Kun Liu, Li Fan, Yidong Li, Xiaofeng Li, Luchao Shi, Benkang Hao, Yichang Xia, Chuanyou Nie, Qingsheng Xin, Yue Shi, Zhenfeng Ma, Lulin Xu, Dawei Liu, Cheng |
author_sort | Wang, Guoliang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7041758 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-70417582020-03-04 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 Wang, Guoliang Huang, Yi Yang, Feilong Tian, Xiaojun Wang, Kun Liu, Li Fan, Yidong Li, Xiaofeng Li, Luchao Shi, Benkang Hao, Yichang Xia, Chuanyou Nie, Qingsheng Xin, Yue Shi, Zhenfeng Ma, Lulin Xu, Dawei Liu, Cheng Aging (Albany NY) Research Paper 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. Impact Journals 2020-02-01 /pmc/articles/PMC7041758/ /pubmed/32007952 http://dx.doi.org/10.18632/aging.102718 Text en Copyright © 2020 Wang et al. http://creativecommons.org/licenses/by/3.0/ 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. |
spellingShingle | Research Paper Wang, Guoliang Huang, Yi Yang, Feilong Tian, Xiaojun Wang, Kun Liu, Li Fan, Yidong Li, Xiaofeng Li, Luchao Shi, Benkang Hao, Yichang Xia, Chuanyou Nie, Qingsheng Xin, Yue Shi, Zhenfeng Ma, Lulin Xu, Dawei Liu, Cheng 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041758/ https://www.ncbi.nlm.nih.gov/pubmed/32007952 http://dx.doi.org/10.18632/aging.102718 |
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