Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana.
Department of Intelligent Systems Engineering, Indiana University, Bloomington, Indiana.
Mol Cancer Res. 2021 Jul;19(7):1168-1181. doi: 10.1158/1541-7786.MCR-20-0883. Epub 2021 Mar 22.
High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand that exacerbate misfolded, unfolded, and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. This study reports that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion, as well as significantly decreased the metastatic growth of ovarian cancer xenografts. Transcriptional profiling of UCHL1-silenced HGSOC cells revealed downregulation of genes implicated with proteasome activity along with upregulation of endoplasmic reticulum stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH), upon silencing of UCHL1, resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1-silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7-APEH-proteasome axis. IMPLICATIONS: This study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC and recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress in solid tumors.
高级别浆液性卵巢癌（HGSOC）的特征是染色体不稳定、DNA 损伤、氧化应激和高代谢需求，这些都会加剧错误折叠、未折叠和受损蛋白质的负担，导致蛋白质毒性增加。然而，维持蛋白质平衡以促进 HGSOC 生长的潜在机制仍知之甚少。本研究报告神经元去泛素化酶，泛素羧基末端水解酶 L1（UCHL1）在 HGSOC 中过表达，并维持蛋白质平衡。UCHL1 在 HGSOC 患者肿瘤和输卵管上皮内癌（HGSOC 前体病变）中表达明显增加。高 UCHL1 水平与更高的肿瘤分级和患者生存不良相关。UCHL1 抑制减少了 HGSOC 细胞的增殖和侵袭，并且显著减少了卵巢癌异种移植物的转移生长。对 UCHL1 沉默的 HGSOC 细胞的转录谱分析显示，与蛋白酶体活性相关的基因下调，同时内质网应激诱导基因上调。沉默 UCHL1 后，蛋白酶体亚单位 alpha 7（PSMA7）和酰基氨基酸肽水解酶（APEH）的表达减少，导致蛋白酶体活性显著降低，蛋白质降解受损，并阻止了 HGSOC 的生长。此外，UCHL1 沉默细胞中多泛素化蛋白的积累导致 mTORC1 活性和蛋白质合成减弱，并诱导末端未折叠蛋白反应。总的来说，这些结果表明 UCHL1 通过 PSMA7-APEH-蛋白酶体轴介导蛋白质平衡来促进 HGSOC 的生长。意义：本研究鉴定了蛋白质平衡网络中的新联系，以靶向 HGSOC 中的蛋白质平衡，并认识到抑制 UCHL1 和 APEH 以增加实体肿瘤中癌细胞对蛋白质毒性应激的敏感性的潜力。
