p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.
p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.
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DOI：
10.1073/pnas.1808314115
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发表时间：
2018-11-13
影响因子：
11.1
通讯作者：
Melino G
中科院分区：
文献类型：
--
作者：
Amelio I;Mancini M;Petrova V;Cairns RA;Vikhreva P;Nicolai S;Marini A;Antonov AA;Le Quesne J;Baena Acevedo JD;Dudek K;Sozzi G;Pastorino U;Knight RA;Mak TW;Melino G
由TP 53基因突变产生的新蛋白在癌细胞中的表达是一个重要的预后因素;然而，p53突变体如何促进癌症进展在很大程度上是未知的。在这里，我们描述了一个分子机制的功能获得突变p53在缺氧的非小细胞肺癌（NSCLC）细胞。我们确定了缺氧诱导因子-1（HIF-1）/突变型p53复合物的存在，对特定的促肿瘤基因亚组进行转录控制，编码细胞外基质（ECM）成分。采用体内癌症模型和分析临床资料，我们证明，这些ECM成分大大有助于协同protumorigenic活性的p53突变体和HIF-1。我们的数据表明，HIF-1/突变型p53串扰是治疗晚期NSCLC的一个创新的潜在治疗靶点。TP 53基因突变和微环境驱动的缺氧诱导因子-1（HIF-1）激活通常发生在肿瘤发生的后期。一个持续的挑战是确定晚期癌症发病机制的分子决定因素，以设计替代的最后一线治疗方案。在这里，我们报告了p53突变体通过与HIF-1合作促进癌症进展来影响肿瘤微环境。我们证明，在非小细胞肺癌（NSCLC）中，p53突变体对HIF-1产生功能获得（GOF）效应，从而调节参与促肿瘤发生功能的选择性基因表达特征。低氧介导的HIF-1激活导致p53突变体/HIF-1复合物的形成，该复合物物理结合SWI/SNF染色质重塑复合物，促进低氧应答基因的选择性子集的表达。p53突变体的缺失损害HIF介导的细胞外基质（ECM）组分（包括VIIa 1型胶原和层粘连蛋白-γ2）的上调，从而影响NSCLC细胞在体外和小鼠模型中的体内致瘤潜力。对手术切除的人NSCLC的分析显示，这种ECM基因特征的表达与仅在携带p53突变的患者中的缺氧肿瘤高度相关，并且与不良预后相关。我们的数据揭示了p53突变体在缺氧肿瘤中的GOF效应，并表明p53和HIF-1的协同活性。这些发现对癌症进展具有重要意义，并可能为晚期NSCLC提供创新的最后一线治疗选择。
Expression in cancer cells of novel proteins generated by mutations in the TP53 gene is an important prognostic factor; however, how p53 mutants promote cancer progression is largely unknown. Here, we describe a molecular mechanism of gain-of-function by mutant p53 in hypoxic non-small cell lung cancer (NSCLC) cells. We identified the existence of a hypoxia-inducible factor-1 (HIF-1)/mutant p53 complex, exerting transcriptional control of a specific subset of protumorigenic genes, codifying for extracellular matrix (ECM) components. Employing in vivo cancer models and analyzing clinical material, we demonstrate that these ECM components substantially contribute to the synergistic protumorigenic activity of p53 mutants and HIF-1. Our data indicate that HIF-1/mutant p53 cross-talk is an innovative potential therapeutic target to treat advanced NSCLC. Mutations in the TP53 gene and microenvironmentally driven activation of hypoxia-inducible factor-1 (HIF-1) typically occur in later stages of tumorigenesis. An ongoing challenge is the identification of molecular determinants of advanced cancer pathogenesis to design alternative last-line therapeutic options. Here, we report that p53 mutants influence the tumor microenvironment by cooperating with HIF-1 to promote cancer progression. We demonstrate that in non-small cell lung cancer (NSCLC), p53 mutants exert a gain-of-function (GOF) effect on HIF-1, thus regulating a selective gene expression signature involved in protumorigenic functions. Hypoxia-mediated activation of HIF-1 leads to the formation of a p53 mutant/HIF-1 complex that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of a selective subset of hypoxia-responsive genes. Depletion of p53 mutants impairs the HIF-mediated up-regulation of extracellular matrix (ECM) components, including type VIIa1 collagen and laminin-γ2, thus affecting tumorigenic potential of NSCLC cells in vitro and in mouse models in vivo. Analysis of surgically resected human NSCLC revealed that expression of this ECM gene signature was highly correlated with hypoxic tumors exclusively in patients carrying p53 mutations and was associated with poor prognosis. Our data reveal a GOF effect of p53 mutants in hypoxic tumors and suggest synergistic activities of p53 and HIF-1. These findings have important implications for cancer progression and might provide innovative last-line treatment options for advanced NSCLC.
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影响因子：
10.5
作者：
Pfister NT;Fomin V;Regunath K;Zhou JY;Zhou W;Silwal-Pandit L;Freed-Pastor WA;Laptenko O;Neo SP;Bargonetti J;Hoque M;Tian B;Gunaratne J;Engebraaten O;Manley JL;Børresen-Dale AL;Neilsen PM;Prives C
通讯作者：
Prives C
影响因子：
56.9
作者：
Ortiz-Urda, S;Garcia, J;Khavari, PA
通讯作者：
Khavari, PA
影响因子：
4.8
作者：
Blagosklonny, MV;An, WG;Neckers, L
通讯作者：
Neckers, L
缺氧介导的 L-2-羟基戊二酸增加可协调对还原应激的代谢反应。
影响因子：
29
作者：
Oldham WM;Clish CB;Yang Y;Loscalzo J
通讯作者：
Loscalzo J
影响因子：
10.5
作者：
Do, Phi M.;Varanasi, Lakshman;Martinez, Luis A.
通讯作者：
Martinez, Luis A.