L’alterata degradazione di YAP1 e IL6ST da parte dell’autofagia chaperon-mediata promuove la proliferazione e la migrazione delle cellule epatiche normali e di epatocarcinoma

È stato dimostrato che l’alterata degradazione del coattivatore trascrizionale YAP1 e IL6ST (trasduttore del segnale della famiglia delle citochine dell'interleuchina 6), due proteine deregolate nel tumore del fegato, promuove la crescita del tumore.
In questo studio dimostriamo che YAP1 e IL6ST sono nuovi substrati dell'autofagia chaperon-mediata (CMA) nel carcinoma epatocellulare dell’uomo (HCC) e nelle linee cellulari degli epatociti.
Questo lavoro rivela un nuovo meccanismo che controlla il turnover di due proteine rilevanti per il tumore del fegato e suggerisce una funzione oncosoppressore della CMA nel fegato, sostenendo lo sfruttamento dell'attività della CMA per scopi diagnostici e terapeutici.
Enrico Desideri, Serena Castelli, Coralie Dorard, Stefanie Toifl, Gian Luca Grazi, Maria Rosa Ciriolo, Manuela Baccarini: Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells. In: Autophagy, 2022, ISSN: 15548627, (Cited by: 0; All Open Access, Hybrid Gold Open Access).

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. Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; CMA: chaperone-mediated autophagy; eMI: endosomal microautophagy; HCC: hepatocellular carcinoma; HSPA8: heat shock protein family A (Hsp70) member 8; IL6ST: interleukin 6 cytokine family signal transducer; JAK: Janus kinase; LAMP1: lysosomal associated membrane protein 1; LAMP2A: lysosomal associated membrane protein 2A; MAPK8: mitogen-activated protein kinase 8; P6: pyridine 6; SQSTM1: sequestosome 1; TUBA: tubulin alpha; VDAC1: voltage dependent anion channel 1; VP: verteporfin; YAP1: Yes1 associated transcriptional regulator. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

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