Lee J H, Han Y-S, Yoon Y M, Yun C W, Yun S P, Kim S M, Kwon H Y, Jeong D, Baek M J, Lee H J, Lee S-J, Han H J, Lee S H
Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.
Oncogene. 2017 Nov 23;36(47):6555-6567. doi: 10.1038/onc.2017.263. Epub 2017 Jul 31.
The cellular prion protein (PrP) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrP degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrP accumulation and tumorigenicity in vivo. PrP was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrP. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrP, thereby increasing PrP ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrP, thereby revealing an essential mechanism that controls PrP levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrP accumulation during tumor progression.
细胞朊蛋白（PrP）与转移、肿瘤进展和复发相关；然而，其作用的精确机制尚未完全清楚。我们的研究发现，PrP降解可降低结直肠癌（CRC）的肿瘤进展。在暴露于缺氧环境的CRC细胞系和人CRC组织中，诱导的热休克70 kDa蛋白1样（HSPA1L）表达可稳定缺氧诱导因子-1α（HIF-1α）蛋白，并促进PrP在体内的积累和致瘤性。PrP通过泛素-蛋白E3连接酶糖蛋白78（GP78）介导的蛋白酶体途径降解，GP78直接与PrP相互作用。然而，缺氧诱导的HSPA1L与GP78相互作用并抑制其功能。HSPA1L敲低促进了GP78与PrP的相互作用，从而增加了PrP的泛素化。因此，GP78被确定为PrP的泛素酶，从而揭示了一种控制CRC中PrP水平的重要机制。我们的结果表明，HSPA1L/HIF-1α/GP78轴在肿瘤进展过程中PrP积累中起关键作用。
