USP7 facilitates SMAD3 autoregulation to repress cancer progression in p53-deficient lung cancer.
USP7 facilitates SMAD3 autoregulation to repress cancer progression in p53-deficient lung cancer.
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USP7促进SMAD3自动调节，抑制p53缺失肺癌的癌症进展。
DOI：
10.1038/s41419-021-04176-8
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发表时间：
2021-09-27
影响因子：
9
通讯作者：
Chen WY
中科院分区：
文献类型：
--
作者：
Huang YT;Cheng AC;Tang HC;Huang GC;Cai L;Lin TH;Wu KJ;Tseng PH;Wang GG;Chen WY
USP 7是最丰富的泛素特异性蛋白酶（USP）之一，在许多细胞事件中发挥多方面的作用，包括致癌途径。大量研究表明，USP 7通过调节MDM 2/MDMX-p53通路，是一个很有前途的肿瘤治疗靶点;然而，关于USP 7在p53缺陷型肿瘤中的功能知之甚少。在这里，我们报告USP 7调节SMAD 3的自动调节，SMAD 3是转化生长因子β（TGFβ）信号传导的关键调节因子，抑制p53缺陷型肺癌的细胞进展。CRISPR/Cas9介导的p53缺陷型肺癌H1299系中USP 7的失活导致体外细胞增殖和体内异种移植肿瘤的晚期细胞增殖。USP 7 KO H1299细胞的全基因组分析（ChIP-seq和RNA-seq）显示SMAD 3自动调节显著降低，包括基因表达降低和相关超级增强子（SE）功能减弱。此外，生物化学测定显示SMAD 3被单泛素缀合，其在USP 7 KO细胞中负调节SMAD 3的DNA结合功能。此外，无细胞和基于细胞的分析进一步表明，USP 7的去泛素化酶活性介导从SMAD 3去除单泛素，并促进SMAD 3-SMAD 4二聚体在SMAD 3位点的DNA结合，从而增强SMAD 3的自身调节。总的来说，我们的研究确定了一种新的机制，通过这种机制，USP 7通过催化SMAD 3去单泛素化，促进SMAD 3的正性自身调节，并抑制p53缺陷型肺癌的癌症进展。
USP7, one of the most abundant ubiquitin-specific proteases (USP), plays multifaceted roles in many cellular events, including oncogenic pathways. Accumulated studies have suggested that USP7, through modulating the MDM2/MDMX-p53 pathway, is a promising target for cancer treatment; however, little is known about the function of USP7 in p53-deficient tumors. Here we report that USP7 regulates the autoregulation of SMAD3, a key regulator of transforming growth factor β (TGFβ) signaling, that represses the cell progression of p53-deficient lung cancer. CRISPR/Cas9-mediated inactivation of USP7 in p53-deficient lung cancer H1299 line resulted in advanced cell proliferation in vitro and in xenograft tumor in vivo. Genome-wide analyses (ChIP-seq and RNA-seq) of USP7 KO H1299 cells reveal a dramatic reduction of SMAD3 autoregulation, including decreased gene expression and blunted function of associated super-enhancer (SE). Furthermore, biochemical assays show that SMAD3 is conjugated by mono-ubiquitin, which negatively regulates the DNA-binding function of SMAD3, in USP7 KO cells. In addition, cell-free and cell-based analyses further demonstrate that the deubiquitinase activity of USP7 mediates the removal of mono-ubiquitin from SMAD3 and facilitates the DNA-binding of SMAD3-SMAD4 dimer at SMAD3 locus, and thus enhance the autoregulation of SMAD3. Collectively, our study identified a novel mechanism by which USP7, through catalyzing the SMAD3 de-monoubiquitination, facilitates the positive autoregulation of SMAD3, and represses the cancer progression of p53-deficient lung cancer.
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DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
64.8
作者：
AKHURST, RJ;FEE, F;BALMAIN, A
通讯作者：
BALMAIN, A
影响因子：
11.4
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
5.3
作者：
COFFEY, RJ;BASCOM, CC;MOSES, HL
通讯作者：
MOSES, HL