SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas.
SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas.
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DOI：
10.1016/j.celrep.2022.110453
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发表时间：
2022-03-01
期刊：
影响因子：
8.8
通讯作者：
Annes JP
中科院分区：
文献类型：
--
作者：
Armstrong N;Storey CM;Noll SE;Margulis K;Soe MH;Xu H;Yeh B;Fishbein L;Kebebew E;Howitt BE;Zare RN;Sage J;Annes JP
遗传性致病性琥珀酸脱氢酶（SDHx）基因突变导致遗传性嗜铬细胞瘤和副神经节瘤肿瘤综合征。综合征型肿瘤表现出琥珀酸升高，这是一种致癌代谢物，被认为通过DNA和组蛋白高甲基化、线粒体扩增和假性缺氧相关基因表达来驱动肿瘤发生。为了询问这种流行的模型，我们破坏了小鼠肾上腺髓质SDHB表达，这概括了人类SDHx肿瘤的几个关键分子特征，包括琥珀酸积累，但不是5 hmC丢失，HIF积累或肿瘤发生。相比之下，伴随SDHB和神经纤维蛋白1肿瘤抑制因子破坏产生SDHX样嗜铬细胞瘤。出乎意料的是，体内消耗2-酮戊二酸（2-OG）双加氧酶辅因子抗坏血酸降低SDHB缺陷细胞的存活率，表明SDHX损失可能是更好地耐受具有高抗氧化能力的组织。与流行的癌代谢物模型相反，琥珀酸积累和2-OG依赖性双加氧酶抑制对于小鼠嗜铬细胞瘤肿瘤发生是不够的，这需要额外的生长调节途径激活。SDHB基因敲除小鼠嗜铬细胞不会致瘤，尽管有足够的琥珀酸积累和SDHB缺陷嗜铬细胞瘤的主要特征。Armstrong等人发现，SDHB和NF 1的双重敲除产生了SDHB样肿瘤，除了肿胀的线粒体和5 hmC的损失之外，还具有琥珀酸和H3 K9 me 3的积累。
Inherited pathogenic succinate dehydrogenase (SDHx) gene mutations cause the hereditary pheochromocytoma and paraganglioma tumor syndrome. Syndromic tumors exhibit elevated succinate, an oncometabolite that is proposed to drive tumorigenesis via DNA and histone hypermethylation, mitochondrial expansion, and pseudohypoxia-related gene expression. To interrogate this prevailing model, we disrupt mouse adrenal medulla SDHB expression, which recapitulates several key molecular features of human SDHx tumors, including succinate accumulation but not 5hmC loss, HIF accumulation, or tumorigenesis. By contrast, concomitant SDHB and the neurofibromin 1 tumor suppressor disruption yields SDHx-like pheochromocytomas. Unexpectedly, in vivo depletion of the 2-oxoglutarate (2-OG) dioxygenase cofactor ascorbate reduces SDHB-deficient cell survival, indicating that SDHx loss may be better tolerated by tissues with high antioxidant capacity. Contrary to the prevailing oncometabolite model, succinate accumulation and 2-OG-dependent dioxygenase inhibition are insufficient for mouse pheochromocytoma tumorigenesis, which requires additional growth-regulatory pathway activation. SDHB knockout in mouse chromaffin cells is not tumorigenic despite ample succinate accumulation and conveyance of cardinal features of SDHB-deficient pheochromocytomas. Armstrong et al. find that dual knockout of SDHB and NF1 yields SDHB-like tumors with accumulation of succinate and H3K9me3, in addition to swollen mitochondria and loss of 5hmC.
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50.3
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Fishbein L;Leshchiner I;Walter V;Danilova L;Robertson AG;Johnson AR;Lichtenberg TM;Murray BA;Ghayee HK;Else T;Ling S;Jefferys SR;de Cubas AA;Wenz B;Korpershoek E;Amelio AL;Makowski L;Rathmell WK;Gimenez-Roqueplo AP;Giordano TJ;Asa SL;Tischler AS;Cancer Genome Atlas Research Network;Pacak K;Nathanson KL;Wilkerson MD
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影响因子：
4
作者：
Chen L;Liu T;Zhang S;Zhou J;Wang Y;Di W
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Di W
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DOI：
10.1007/s13361-017-1809-6
发表时间：
2018-01
影响因子：
3.2
作者：
Bokhart MT;Nazari M;Garrard KP;Muddiman DC
通讯作者：
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