PO.MCB03.03 · 分子与细胞生物学
泛素特异性肽酶37（USP37）促进复制应激耐受以推动前列腺癌的肿瘤发生
Ubiquitin specific peptidase 37 (USP37) facilitate Replication stress tolerance to promote prostate cancer oncogenesis
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摘要 Abstract
中文摘要
数项报道提示DUBs（去泛素化酶）在多种癌症中高度升高，逆转泛素化过程并负责致癌蛋白的稳定化。在DUBs中，泛素特异性肽酶37（USP37）是泛素特异性蛋白酶家族中研究最少的成员之一。USP37控制肿瘤发生的众多方面，包括如我们近期研究所报道的稳定许多致癌蛋白。前列腺癌（PC）是男性中最常见的癌症诊断，仍是男性癌症死亡的主要原因。然而，USP37在前列腺癌中的生物学功能仍不明确。对TCGA数据的分析表明USP37的过表达与前列腺癌患者无进展生存期（PFS）缩短相关。对前列腺癌细胞（DU145）的质谱（MS）分析表明，敲低USP37后一组独特的基因发生改变。生存数据表明USP37过表达赋予生存优势，而其耗竭增强PC细胞对细胞杀伤的敏感性。在基因毒性应激下，USP37过表达细胞能够比对照细胞或USP37被耗竭的细胞更迅速地解析DNA损伤焦点。USP37耗竭导致γH2AX和53BP1 DNA损伤焦点的解析减少，这表明细胞进行组成性DNA复制的能力下降。如我们的MS分析所见，发现USP37与不同的复制因子相互作用，包括许多先前报道的伙伴。我们进一步通过分析USP37过表达是否与疾病进展相关，将我们的数据与PC患者的存档组织块相关联。目前的数据提示USP37是PC中复制应激耐受所必需的，并且是停靠额外复制因子和稳定DNA复制叉所必需的。当前数据提供了USP37在PC细胞中调控的新通路，这强化了在前列腺癌背景下针对USP37的靶向策略的开发。
查看英文原文 English abstract
Several reports have suggested that the DUBs (Deubiquitinating enzymes) are highly-elevated in various cancers, Reverses the process of ubiquitination and are responsible for stabilization of oncoproteins. Among DUBs, Ubiquitin-specific peptidase 37 (USP37) is one of the least studied member of the Ubiquitin specific protease family. USP37 controls numerous aspects of oncogenesis, including stabilizing many oncoproteins as reported in our recent studies. Prostate cancer (PC) is the most common cancer diagnosis made in men remains the leading cause of cancer death in men. However, the biological functions of USP37 in prostate cancer remain unclear. Analysis of TCGA data indicated that overexpression of USP37 correlated with reduced progression free survival (PFS) in prostate cancer patients. Mass spectrometry (MS) analysis of Prostate cancer cells (DU145) indicated that distinct set of genes were altered on knockdown of USP37. Survival Data indicate that USP37 overexpression confers survival advantage while its depletion enhances sensitivity for cell killing in PC cells. USP37 overexpressing cells were able to resolve DNA damage foci much more rapidly than the control cells or cells in which USP37 was depleted in response to genotoxic stress. USP37 depletion results in reduced resolution of gamma H2AX and 53BP1 DNA damage foci which indicates the reduced ability of cells to carry out constitutive DNA replication. USP37 was found to interact with different replication factors as also seen in our MS analysis including many previously reported partners. We further correlated our data with archived tissue blocks of PC patients by analyzing if USP37 overexpression correlated with disease progression. Present data suggests that USP37 is required for tolerance of replication stress in PC and is required to dock additional replication factors and stabilize DNA replication fork. The current data provides novel pathways regulated by USP37 in PC cells which reinforce development of targeting strategies against USP37 in context of Prostate Cancer.
利益披露 Disclosure
S. K. Das, None..
L. Malhotra, None..
G. Dagar, None..
T. Haritwal, None..
A. Batra, None..
M. Singh, None.