微管结合蛋白1轻链3伽玛（MAP1LC3C或LC3C）是微管关联蛋白家族的成员，对于自噬体的形成和货物的溶酶体降解至关重要。LC3C具有肿瘤抑制活性，其表达取决于肾癌抑制子如von Hippel-Lindau蛋白（VHL）和依葉蛋白（FLCN）。最近的研究表明，LC3C自噬作用受非常规上游调节复合物的调控，并且靶向与癌细胞干性相关的细胞分裂中环，用于降解。在这里，我们显示LC3C丧失导致溶酶体的周围定位和溶酶体外分泌（LE），这个过程与LC3C的自噬活性无关。低和高LE的同源细胞分析显示了显著的转录组重编程，改变了Zn相关基因的表达和Polycomb抑制复合体2（PRC2）的活性，并伴随显著降低细胞内Zn。此外，代谢组学分析显示，氨基酸稳态水平发生了改变。具有增强LE的细胞显示出增加的肿瘤起始性，形成穿梭移植模型中的侵袭性肿瘤。免疫细胞化学检测在人类透明细胞肾癌（ccRCC）中发现癌细胞质膜上Lysosomal Associated Membrane Protein 1（LAMP1）水平较高，Zn水平降低，这表明LE在ccRCC中发生，可能导致Zn的损失。这些数据表明，溶酶体定位和Zn代谢的重编程与表观遗传重塑有关，在一部分肿瘤传播癌细胞中是LC3C肿瘤抑制活性的重要方面。版权所有©2023年作者。由Elsevier Inc出版。保留所有权利。

Microtubule Associated Protein 1 Light Chain 3 Gamma (MAP1LC3C or LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as von Hippel-Lindau protein (VHL) and folliculin (FLCN). Recently We demonstrated that LC3C autophagy is regulated by noncanonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE). This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Additionally, metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show increased tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of Lysosomal Associated Membrane Protein 1 (LAMP1) on the plasma membrane of cancer cells in human clear cell renal cell carcinoma (ccRCC) and reduced levels of Zn, suggesting that LE occurs in ccRCC, potentially contributing to the loss of Zn. These data indicate that the reprogramming of lysosomal localization and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating cancer cells is an important aspect of tumor suppressing activity of LC3C.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.