BAP1 is a novel regulator of HIF-1α.
BAP1 is a novel regulator of HIF-1α.
复制标题
BAP1 是 HIF-1α 的新型调节剂。
DOI：
10.1073/pnas.2217840120
复制
发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Carbone, Michele
中科院分区：
文献类型：
--
作者：
Bononi, Angela;Wang, Qian;Zolondick, Alicia A.;Bai, Fang;Steele-Tanji, Mika;Suarez, Joelle S.;Pastorino, Sandra;Sipes, Abigail;Signorato, Valentina;Ferro, Angelica;Novelli, Flavia;Kim, Jin-Hee;Minaai, Michael;Takinishi, Yasutaka;Pellegrini, Laura;Napolitano, Andrea;Xu, Ronghui;Farrar, Christine;Goparaju, Chandra;Bassi, Cristian;Negrini, Massimo;Pagano, Ian;Sakamoto, Greg;Gaudino, Giovanni;Pass, Harvey I.;Onuchic, Jose N.;Yang, Haining;Carbone, Michele
BAP1 调节调节基因组稳定性和细胞死亡的关键细胞途径。 BAP1突变一方面有利于恶性转化和间皮瘤的发展；另一方面，BAP1突变也有利于间皮瘤的发生。另一方面，它们可以降低间皮瘤的侵袭性。通过研究这一明显的悖论，我们发现 BAP1 在缺氧条件下去泛素化并稳定 HIF-1α；因此，BAP1失活突变显着降低HIF-1α。鉴于HIF-1α在促进肿瘤侵袭中的关键作用，我们提出：1）携带种系BAP1突变的个体的肿瘤细胞和肿瘤微环境中BAP1的减少可能有助于减少间皮瘤的侵袭并显着改善预后； 2）肿瘤发生后靶向野生型BAP1可能是降低缺氧组织中HIF-1α蛋白水平并损害肿瘤生长的一种新的有效策略。 BAP1 是一种强大的肿瘤抑制基因，其特征是单倍体不足。携带种系 BAP1 突变的个体通常会患上间皮瘤，这是一种覆盖肺、心包和腹腔的浆膜层的侵袭性恶性肿瘤。有趣的是，种系 BAP1 突变携带者中发生的间皮瘤侵袭性较小，并且这些患者的生存率显着提高。我们研究了肿瘤抑制基因的明显悖论，当该基因突变时，会导致侵袭性较低的间皮瘤。我们发现，具有双等位基因 BAP1 突变的间皮瘤活检显示核 HIF-1α 染色缺失。我们证明，在缺氧期间，BAP1 结合、去泛素化并稳定 HIF-1α，HIF-1α 是缺氧反应和肿瘤细胞侵袭的主要调节因子。此外，来自携带种系 BAP1 突变的个体的原代细胞和使用 siRNA 沉默 BAP1 的原代细胞在缺氧条件下降低了 HIF-1α 蛋白水平。计算模型和免疫共沉淀实验表明，BAP1 残基 I675、F678、I679 和 L691（包含 C 端结构域核定位信号）突变为 A，消除了与 HIF-1α 的相互作用。我们发现 BAP1 与 HIF-1α 的 N 末端区域结合，其中 HIF-1α 与 DNA 结合并与 HIF-1β 二聚化，形成异二聚体反式激活复合物 HIF。我们的数据表明 BAP1 是缺氧时 HIF-1α 的关键正调节因子。我们提出，携带双等位基因 BAP1 突变的间皮瘤细胞中 HIF-1α 活性的显着降低，伴随着含有种系 BAP1 突变的缺氧组织中 HIF-1α 活性的显着降低，有助于降低种系 BAP1 突变携带者中发生的间皮瘤的侵袭性并提高其生存率。
BAP1 modulates crucial cellular pathways that regulate genomic stability and cell death. BAP1 mutations on the one hand favor malignant transformation and mesothelioma development; on the other hand, they reduce mesothelioma aggressiveness. Investigating this apparent paradox, we discovered that BAP1 deubiquitylates and stabilizes HIF-1α in hypoxia; thus, BAP1 inactivating mutations significantly reduce HIF-1α. Given the critical role of HIF-1α in promoting tumor invasion, we propose that: 1) Reduced BAP1 in the tumor cells and tumor microenvironment of individuals carrying germline BAP1 mutations may contribute to the reduced invasion and the significantly improved prognosis of mesothelioma; 2) targeting wild-type BAP1 after tumor development could be a novel effective strategy to reduce HIF-1α protein levels in hypoxic tissues and impair tumor growth. BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.
登录
查看更多内容
影响因子：
4.5
作者：
Carbone M;Flores EG;Emi M;Johnson TA;Tsunoda T;Behner D;Hoffman H;Hesdorffer M;Nasu M;Napolitano A;Powers A;Minaai M;Baumann F;Bryant-Greenwood P;Lauk O;Kirschner MB;Weder W;Opitz I;Pass HI;Gaudino G;Pastorino S;Yang H
通讯作者：
Yang H
影响因子：
28.2
作者：
Carbone M;Harbour JW;Brugarolas J;Bononi A;Pagano I;Dey A;Krausz T;Pass HI;Yang H;Gaudino G
通讯作者：
Gaudino G
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
DOI：
10.1073/pnas.2019652117
发表时间：
2020-12-29
影响因子：
11.1
作者：
Bononi A;Goto K;Ak G;Yoshikawa Y;Emi M;Pastorino S;Carparelli L;Ferro A;Nasu M;Kim JH;Suarez JS;Xu R;Tanji M;Takinishi Y;Minaai M;Novelli F;Pagano I;Gaudino G;Pass HI;Groden J;Grzymski JJ;Metintas M;Akarsu M;Morrow B;Hassan R;Yang H;Carbone M
通讯作者：
Carbone M
影响因子：
8
作者：
Goparaju, C. M.;Blasberg, J. D.;Volinia, S.;Palatini, J.;Ivanov, S.;Donington, J. S.;Croce, C.;Carbone, M.;Yang, H.;Pass, H. I.
通讯作者：
Pass, H. I.