Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis.
Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis.
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DOI：
10.1038/s41467-017-02245-1
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发表时间：
2017-12-11
影响因子：
16.6
通讯作者：
Matakidou A
中科院分区：
文献类型：
--
作者：
Espana-Agusti J;Warren A;Chew SK;Adams DJ;Matakidou A
VHL（Von Hippel Lindau）肿瘤抑制因子的失活长期以来被认为是透明细胞肾癌（ccRCC）发病机制所必需的;然而，转化的分子机制和额外遗传命中的要求仍不清楚。在这里，我们表明，VHL的损失单独的结果在DNA复制应力和损伤积累，限制细胞生长和转化的影响。相比之下，染色质重塑因子PBRM 1（在40%的ccRCC中突变）的伴随损失挽救了VHL诱导的复制应激，维持了细胞适应性并允许增殖。与这些数据一致，我们证明了小鼠肾脏中Vhl和Pbrm 1的组合缺失足以发展完全渗透的多灶性癌，密切模仿人ccRCC。我们的研究结果说明了VHL和PBRM 1如何合作来驱动肾脏转化，并揭示复制应激是所有VHL突变肾癌的潜在脆弱性，可以在治疗上加以利用。VHL突变与肾透明细胞癌有关，但涉及的分子机制仍不清楚。在这里，作者产生了一个密切模仿人类疾病的小鼠模型，并表明VHL损失诱导DNA复制应激，这是由PBRM 1的伴随损失允许转化拯救。
Inactivation of the VHL (Von Hippel Lindau) tumour suppressor has long been recognised as necessary for the pathogenesis of clear cell renal cancer (ccRCC); however, the molecular mechanisms underlying transformation and the requirement for additional genetic hits remain unclear. Here, we show that loss of VHL alone results in DNA replication stress and damage accumulation, effects that constrain cellular growth and transformation. By contrast, concomitant loss of the chromatin remodelling factor PBRM1 (mutated in 40% of ccRCC) rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. In line with these data we demonstrate that combined deletion of Vhl and Pbrm1 in the mouse kidney is sufficient for the development of fully-penetrant, multifocal carcinomas, closely mimicking human ccRCC. Our results illustrate how VHL and PBRM1 co-operate to drive renal transformation and uncover replication stress as an underlying vulnerability of all VHL mutated renal cancers that could be therapeutically exploited. Mutations in VHL have been linked to clear cell renal cancer, but the molecular mechanisms involved remain unclear. Here the authors generate a mouse model closely mimicking the human disease and show that VHL loss induces DNA replication stress that is rescued by the concomitant loss of PBRM1 permitting transformation.
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小鼠肾细胞癌建模：Bap1 和 Pbrm1 失活驱动肿瘤分级。
影响因子：
28.2
作者：
Gu YF;Cohn S;Christie A;McKenzie T;Wolff N;Do QN;Madhuranthakam AJ;Pedrosa I;Wang T;Dey A;Busslinger M;Xie XJ;Hammer RE;McKay RM;Kapur P;Brugarolas J
通讯作者：
Brugarolas J
影响因子：
64.8
作者：
AUKLAND, K;KROG, J
通讯作者：
KROG, J
影响因子：
4.6
作者：
Guo, Ge;Yang, Jian;Smith, Austin
通讯作者：
Smith, Austin
影响因子：
11.2
作者：
Hell, Michael P.;Duda, Maria;Krek, Wilhelm
通讯作者：
Krek, Wilhelm
DOI：
10.1073/pnas.91.21.9700
发表时间：
1994-10-11
影响因子：
11.1
作者：
HERMAN, JG;LATIF, F;BAYLIN, SB
通讯作者：
BAYLIN, SB