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Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma
bioRxiv - Cancer Biology Pub Date : 2020-10-09 , DOI: 10.1101/2020.09.28.316810
Apoorva Tangri , Kinzie Lighty , Jagadish Loganathan , Fahmi Mesmar , Ram Podicheti , Chi Zhang , Marcin Iwanicki , Harikrishna Nakshatri , Sumegha Mitra

High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand, which 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. In this study, we report 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 through the outer layers of omentum as well as significantly decreased the in vivo metastatic tumor growth in ovarian cancer xenografts. Transcriptional profiling of UCHL1 silenced HGSOC cells revealed the down-regulation of genes implicated with proteasome activity along with the upregulation of endoplasmic reticulum (ER) stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH) 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. It recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress and as novel alternative therapeutic approaches.

中文翻译:

去泛素酶UCHL1通过PSMA7-APEH-蛋白酶体轴在高级浆液性卵巢癌中维持蛋白质稳态。

高度浆液性卵巢癌(HGSOC)的特征在于染色体不稳定,DNA损伤,氧化应激和高代谢需求,这加剧了错误折叠,展开和破坏的蛋白质负担,从而导致蛋白毒性增加。然而,维持蛋白质稳态以促进HGSOC生长的基本机制仍然知之甚少。在这项研究中,我们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,并维持蛋白质稳态。在HGSOC患者肿瘤和浆液性输卵管上皮内癌(HGSOC前体病变)中,UCHL1表达显着增加。较高的UCHL1水平与较高的肿瘤等级和较差的患者生存率相关。UCHL1抑制作用减少了HGSOC细胞通过大网膜外层的增殖和侵袭,并显着降低了卵巢癌异种移植物中体内转移性肿瘤的生长。UCHL1沉默的HGSOC细胞的转录谱分析揭示了与蛋白酶体活性有关的基因的下调以及内质网(ER)应激诱导的基因的上调。蛋白酶体亚基α7(PSMA7)和酰基氨基酰基肽水解酶(APEH)的表达降低导致蛋白酶体活性显着降低,蛋白降解受损和HGSOC生长废止。此外,在UCHL1沉默的细胞中聚泛素化蛋白的积累导致mTORC1活性和蛋白合成减弱,并诱导末端未折叠蛋白反应。总的来说,这些结果表明,UCHL1通过通过PSMA7-APEH-蛋白酶体轴介导蛋白质稳态来促进HGSOC的生长。启示:这项研究确定了蛋白稳态网络中靶向HGSOC中蛋白质稳态的新型链接。它认识到抑制UCHL1和APEH可能使癌细胞对蛋白毒性应激敏感的潜力,并作为新的替代治疗方法。
更新日期:2020-10-11
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