黑色素瘤细胞改变分化相关转录库以逃避治疗并促进转移扩散的固有能力已被广泛接受，并被称为表型转换。然而，细胞行为的这些方面是如何控制的仍然很大程度上难以捉摸。在这里，我们表明，半胱氨酸的可用性，无论是来自溶酶体（CTNS依赖性）还是外源性来源（SLC7A11依赖性或N-乙酰半胱氨酸），都通过作用于黑色素细胞主调节因子MITF来控制黑色素瘤分化相关途径。功能数据表明，低半胱氨酸可用性会降低 MITF 水平并损害溶酶体功能，这会影响肿瘤铁死亡敏感性，但会改善体内转移扩散。从机制上讲，半胱氨酸限制条件降低乙酰辅酶A水平，从而减少黑素细胞限制性MITF启动子处p300介导的H3K27乙酰化，从而形成控制MITF水平和下游溶酶体功能的半胱氨酸前馈调节。这些发现共同表明，半胱氨酸稳态通过维持 MITF 水平和溶酶体功能来控制黑色素瘤分化，从而防止铁死亡并限制转移扩散。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.