Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells

Enrico Desideri; Serena Castelli; Coralie Dorard; Stefanie Toifl; Gian Luca Grazi; Maria Rosa Ciriolo; Manuela Baccarini

doi:10.1080/15548627.2022.2063004

Titel

Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells

Autor*in

Enrico Desideri

Department für Mikrobiologie, Immunbiologie und Genetik (bis 2023-12-31), Zentrum für Molekulare Biologie (bis 2023-12-31), Universität Wien

Serena Castelli

Department of Biology, University of Rome “Tor Vergata”

Coralie Dorard

Department für Mikrobiologie, Immunbiologie und Genetik (bis 2023-12-31), Zentrum für Molekulare Biologie (bis 2023-12-31), Universität Wien

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Abstract

Impaired degradation of the transcriptional coactivator YAP1 and IL6ST (interleukin 6 cytokine family signal transducer), two proteins deregulated in liver cancer, has been shown to promote tumor growth. Here, we demonstrate that YAP1 and IL6ST are novel substrates of chaperone-mediated autophagy (CMA) in human hepatocellular carcinoma (HCC) and hepatocyte cell lines. Knockdown of the lysosomal CMA receptor LAMP2A increases protein levels of YAP1 and IL6ST, without changes in mRNA expression. Additionally, both proteins show KFERQ-dependent binding to the CMA chaperone HSPA8 and accumulate into isolated lysosomes after stimulation of CMA by prolonged starvation. We further show that LAMP2A downregulation promotes the proliferation and migration in HCC cells and a human hepatocyte cell line, and that it does so in a YAP1- and IL6ST-dependent manner. Finally, LAMP2A expression is downregulated, and YAP1 and IL6ST expression is upregulated, in human HCC biopsies. Taken together, our work reveals a novel mechanism that controls the turnover of two cancer-relevant proteins and suggests a tumor suppressor function of CMA in the liver, advocating for the exploitation of CMA activity for diagnostic and therapeutic purposes.

Stichwort

Chaperone-mediated autophagyhepatocellular carcinomaIL6STKFERQ motifLAMP2Amigrationproliferationprotein degradationYAP1

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

https://phaidra.univie.ac.at/o:1632174

DOI

10.1080/15548627.2022.2063004

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