Feedforward cysteine regulation maintains melanoma differentiation state and limits metastatic spread.

Autor:	Yu D; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Liang J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Widlund HR; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: hwidlund@bwh.harvard.edu., Puigserver P; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: pere_puigserver@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Jul 23; Vol. 43 (7), pp. 114484. Date of Electronic Publication: 2024 Jul 10.
DOI:	10.1016/j.celrep.2024.114484
Abstrakt:	The inherent ability of melanoma cells to alter the differentiation-associated transcriptional repertoire to evade treatment and facilitate metastatic spread is well accepted and has been termed phenotypic switching. However, how these facets of cellular behavior are controlled remains largely elusive. Here, we show that cysteine availability, whether from lysosomes (CTNS-dependent) or exogenously derived (SLC7A11-dependent or as N-acetylcysteine), controls melanoma differentiation-associated pathways by acting on the melanocyte master regulator MITF. Functional data indicate that low cysteine availability reduces MITF levels and impairs lysosome functions, which affects tumor ferroptosis sensitivity but improves metastatic spread in vivo. Mechanistically, cysteine-restrictive conditions reduce acetyl-CoA levels to decrease p300-mediated H3K27 acetylation at the melanocyte-restricted MITF promoter, thus forming a cysteine feedforward regulation that controls MITF levels and downstream lysosome functions. These findings collectively suggest that cysteine homeostasis governs melanoma differentiation by maintaining MITF levels and lysosome functions, which protect against ferroptosis and limit metastatic spread. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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