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TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy

Autophagy plays a pivotal role in physiology and pathophysiology, including cancer. Mechanisms of autophagy dysregulation in cancer remain elusive. Loss of function of TRIM28, a multifunction protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiolog...

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Autores principales: Song, Tanjing, Lv, Suli, Ma, Xianyun, Zhao, Xuefeng, Fan, Li, Zou, Qingli, Li, Neng, Yan, Yingying, Zhang, Wen, Sun, Lidong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141522/
https://www.ncbi.nlm.nih.gov/pubmed/36935008
http://dx.doi.org/10.1016/j.jbc.2023.104621
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author Song, Tanjing
Lv, Suli
Ma, Xianyun
Zhao, Xuefeng
Fan, Li
Zou, Qingli
Li, Neng
Yan, Yingying
Zhang, Wen
Sun, Lidong
author_facet Song, Tanjing
Lv, Suli
Ma, Xianyun
Zhao, Xuefeng
Fan, Li
Zou, Qingli
Li, Neng
Yan, Yingying
Zhang, Wen
Sun, Lidong
author_sort Song, Tanjing
collection PubMed
description Autophagy plays a pivotal role in physiology and pathophysiology, including cancer. Mechanisms of autophagy dysregulation in cancer remain elusive. Loss of function of TRIM28, a multifunction protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiology of kidney malignancy is unclear. In this study, we show TRIM28 retards kidney cancer cell proliferation through inhibiting autophagy. Mechanistically, we find TRIM28 promotes ubiquitination and proteasome-mediated degradation of transcription factor TFE3, which is critical for autophagic gene expression. Genetic activation of TFE3 due to gene fusion is known to cause human kidney malignancy, but whether and how transcription activation by TFE3 involves chromatin changes is unclear. Here, we find another mode of TFE3 activation in human renal carcinoma. We find that TFE3 is constitutively localized to the cell nucleus in human and mouse kidney cancer, where it increases autophagic gene expression and promotes cell autophagy as well as proliferation. We further uncover that TFE3 interacts with and recruits histone H3K27 demethylase KDM6A for autophagic gene upregulation. We reveal that KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27. Collectively, in this study, we identify a functional TRIM28–TFE3–KDM6A signal axis, which plays a critical role in kidney cancer cell autophagy and proliferation.
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spelling pubmed-101415222023-04-29 TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy Song, Tanjing Lv, Suli Ma, Xianyun Zhao, Xuefeng Fan, Li Zou, Qingli Li, Neng Yan, Yingying Zhang, Wen Sun, Lidong J Biol Chem Research Article Autophagy plays a pivotal role in physiology and pathophysiology, including cancer. Mechanisms of autophagy dysregulation in cancer remain elusive. Loss of function of TRIM28, a multifunction protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiology of kidney malignancy is unclear. In this study, we show TRIM28 retards kidney cancer cell proliferation through inhibiting autophagy. Mechanistically, we find TRIM28 promotes ubiquitination and proteasome-mediated degradation of transcription factor TFE3, which is critical for autophagic gene expression. Genetic activation of TFE3 due to gene fusion is known to cause human kidney malignancy, but whether and how transcription activation by TFE3 involves chromatin changes is unclear. Here, we find another mode of TFE3 activation in human renal carcinoma. We find that TFE3 is constitutively localized to the cell nucleus in human and mouse kidney cancer, where it increases autophagic gene expression and promotes cell autophagy as well as proliferation. We further uncover that TFE3 interacts with and recruits histone H3K27 demethylase KDM6A for autophagic gene upregulation. We reveal that KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27. Collectively, in this study, we identify a functional TRIM28–TFE3–KDM6A signal axis, which plays a critical role in kidney cancer cell autophagy and proliferation. American Society for Biochemistry and Molecular Biology 2023-03-18 /pmc/articles/PMC10141522/ /pubmed/36935008 http://dx.doi.org/10.1016/j.jbc.2023.104621 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Song, Tanjing
Lv, Suli
Ma, Xianyun
Zhao, Xuefeng
Fan, Li
Zou, Qingli
Li, Neng
Yan, Yingying
Zhang, Wen
Sun, Lidong
TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy
title TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy
title_full TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy
title_fullStr TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy
title_full_unstemmed TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy
title_short TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy
title_sort trim28 represses renal cell carcinoma cell proliferation by inhibiting tfe3/kdm6a-regulated autophagy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141522/
https://www.ncbi.nlm.nih.gov/pubmed/36935008
http://dx.doi.org/10.1016/j.jbc.2023.104621
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