Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Department of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
J Biol Chem. 2023 May;299(5):104663. doi: 10.1016/j.jbc.2023.104663. Epub 2023 Mar 30.
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 and folliculin. Recently, we demonstrated that LC3C autophagy is regulated by noncanonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cell 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 zinc (Zn)-related genes and activity of polycomb repressor complex 2, accompanied by a robust decrease in intracellular Zn. In addition, 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 on the plasma membrane of cancer cells in human clear cell renal cell carcinoma and reduced levels of Zn, suggesting that LE occurs in clear cell renal cell carcinoma, 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.
微管相关蛋白 1 轻链 3 伽马（MAP1LC3C 或 LC3C）是微管相关蛋白家族的成员，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，其表达依赖于肾癌细胞肿瘤抑制因子，如 von Hippel-Lindau 蛋白和滤泡素。最近，我们证明了 LC3C 自噬受非典型上游调控复合物的调控，并与癌细胞干性相关的分裂中期环上的降解靶标有关。在这里，我们表明 LC3C 的缺失会导致溶酶体的外周定位和溶酶体胞吐作用（LE）。这个过程与 LC3C 的自噬活性无关。对 LE 低和高的同基因细胞进行分析表明，锌（Zn）相关基因的表达和多梳抑制复合物 2 的活性发生了大量转录组重编程，伴随着细胞内 Zn 的显著减少。此外，代谢组学分析显示氨基酸稳态水平发生改变。LE 增强的细胞表现出更高的肿瘤起始特性，并在异种移植模型中形成侵袭性肿瘤。免疫细胞化学在人肾透明细胞癌的癌细胞质膜上鉴定到高水平的溶酶体相关膜蛋白 1 和 Zn 水平降低，提示 LE 发生在肾透明细胞癌中，可能导致 Zn 的丢失。这些数据表明，溶酶体定位和 Zn 代谢的重编程与肿瘤传播癌细胞中表观遗传重塑有关，是 LC3C 肿瘤抑制活性的一个重要方面。
