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Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation

RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor and frequently inactivated by promoter hypermethylation in hepatocellular carcinoma (HCC). Autophagy is to degrade misfolded or aggregated proteins and dysfunctional organelles. Autophagy defects enhance oxidative stress and g...

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Autores principales: Li, Wenjiao, Yue, Fei, Dai, Yuan, Shi, Boyun, Xu, Guibin, Jiang, Xianhan, Zhou, Xinke, Pfeifer, Gerd P., Liu, Leyuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748129/
https://www.ncbi.nlm.nih.gov/pubmed/30315205
http://dx.doi.org/10.1038/s41418-018-0211-7
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author Li, Wenjiao
Yue, Fei
Dai, Yuan
Shi, Boyun
Xu, Guibin
Jiang, Xianhan
Zhou, Xinke
Pfeifer, Gerd P.
Liu, Leyuan
author_facet Li, Wenjiao
Yue, Fei
Dai, Yuan
Shi, Boyun
Xu, Guibin
Jiang, Xianhan
Zhou, Xinke
Pfeifer, Gerd P.
Liu, Leyuan
author_sort Li, Wenjiao
collection PubMed
description RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor and frequently inactivated by promoter hypermethylation in hepatocellular carcinoma (HCC). Autophagy is to degrade misfolded or aggregated proteins and dysfunctional organelles. Autophagy defects enhance oxidative stress and genome instability to promote tumorigenesis. Activating autophagy flux by increasing levels of the RASSF1A-interacting microtubule-associated protein 1 S (MAP1S) leads to suppression of HCC in addition to extending lifespans. Here we tested whether RASSF1A itself functions as a HCC suppressor and activates autophagy similarly as MAP1S does. We show that RASSF1A deletion leads to an acceleration of diethylnitrosamine-induced HCC and a 31% reduction of median survival times in mice. RASSF1A enhances autophagy initiation by suppressing PI3K-AKT-mTOR through the Hippo pathway-regulatory component MST1 and promotes autophagy maturation by recruiting autophagosomes on RASSF1A-stabilized acetylated microtubules through MAP1S. RASSF1A deletion causes a blockade of autophagy flux. Therefore, RASSF1A may suppress HCC and improve survival by activating autophagy flux.
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spelling pubmed-67481292019-09-18 Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation Li, Wenjiao Yue, Fei Dai, Yuan Shi, Boyun Xu, Guibin Jiang, Xianhan Zhou, Xinke Pfeifer, Gerd P. Liu, Leyuan Cell Death Differ Article RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor and frequently inactivated by promoter hypermethylation in hepatocellular carcinoma (HCC). Autophagy is to degrade misfolded or aggregated proteins and dysfunctional organelles. Autophagy defects enhance oxidative stress and genome instability to promote tumorigenesis. Activating autophagy flux by increasing levels of the RASSF1A-interacting microtubule-associated protein 1 S (MAP1S) leads to suppression of HCC in addition to extending lifespans. Here we tested whether RASSF1A itself functions as a HCC suppressor and activates autophagy similarly as MAP1S does. We show that RASSF1A deletion leads to an acceleration of diethylnitrosamine-induced HCC and a 31% reduction of median survival times in mice. RASSF1A enhances autophagy initiation by suppressing PI3K-AKT-mTOR through the Hippo pathway-regulatory component MST1 and promotes autophagy maturation by recruiting autophagosomes on RASSF1A-stabilized acetylated microtubules through MAP1S. RASSF1A deletion causes a blockade of autophagy flux. Therefore, RASSF1A may suppress HCC and improve survival by activating autophagy flux. Nature Publishing Group UK 2018-10-12 2019-08 /pmc/articles/PMC6748129/ /pubmed/30315205 http://dx.doi.org/10.1038/s41418-018-0211-7 Text en © The Authors 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Li, Wenjiao
Yue, Fei
Dai, Yuan
Shi, Boyun
Xu, Guibin
Jiang, Xianhan
Zhou, Xinke
Pfeifer, Gerd P.
Liu, Leyuan
Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation
title Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation
title_full Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation
title_fullStr Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation
title_full_unstemmed Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation
title_short Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation
title_sort suppressor of hepatocellular carcinoma rassf1a activates autophagy initiation and maturation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748129/
https://www.ncbi.nlm.nih.gov/pubmed/30315205
http://dx.doi.org/10.1038/s41418-018-0211-7
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