Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity.
Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity.
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DOI：
10.1073/pnas.2110348119
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发表时间：
2022-07-19
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
这里报道的主要发现是乙酰化将超氧化物歧化酶2（SOD 2）从线粒体抗氧化剂转化为核组蛋白脱甲基酶。功能的变化涉及铁的结合，而不是典型的辅因子锰。与充分表征的组蛋白脱甲基酶不同，FeSOD 2使用H2 O2作为底物，H2 O2通常在缺氧肿瘤小生境中增加。沿着这些路线，我们发现，核FeSOD 2促进谱系可塑性很大程度上是通过促进与上皮-间充质转化和干细胞重编程相关的基因表达的再激活。总之，我们的研究结果提供了证据，支持乙酰化依赖的细胞核特异性功能的SOD 2与更多的致瘤性和转移性癌细胞表型的出现。超氧化物歧化酶-2（SOD 2）在癌症生物学中的二分行为早已被认识，最近与酶的不同翻译后形式有关。然而，其促肿瘤功能的独特活性尚未被描述。在这里，我们报告说，乙酰化，这样的翻译后修饰（PTM）之一，增加SOD 2铁的亲和力，有效地改变这种酶的生化功能从抗氧化剂的脱甲基酶。乙酰化的铁结合SOD 2定位于细胞核，通过去除抑制性表观遗传标记如H3 K9 me 3和H3 K927 me 3来促进干细胞基因表达。特别是，H3 K9 me 3被特异性地从Nanog和Oct-4上游的调控区中去除，这两种多能性因子参与癌症干细胞重编程。表型上，表达核靶向SOD 2（NLS-SOD 2）的细胞具有增加的克隆形成性和转移潜力。作为H3脱甲基酶工作的FeSOD 2需要H2 O2作为底物，这与典型脱甲基酶的辅因子（即，氧和2-酮戊二酸）在肿瘤细胞中比在正常组织中更丰富。因此，我们的研究结果表明，FeSOD 2是一种脱甲基酶，在促进癌症向转移表型演变方面具有独特的活性和功能。
The main finding reported here is that acetylation converts superoxide dismutase-2 (SOD2) from a mitochondrial antioxidant to a nuclear histone demethylase. The change in function involves the binding of iron instead of the canonical cofactor manganese. Unlike well-characterized histone demethylases, FeSOD2 uses H2O2, which is typically increased in hypoxic tumor niches, as substrate. Along these lines, we found that nuclear FeSOD2 promotes lineage plasticity largely by facilitating the reactivation of gene expression associated with epithelial-to-mesenchymal transition and stemness reprogramming. Together, our results provide evidence in support of an acetylation-dependent nucleus-specific function of SOD2 associated with the emergence of more tumorigenic and metastatic cancer cell phenotypes. The dichotomous behavior of superoxide dismutase-2 (SOD2) in cancer biology has long been acknowledged and more recently linked to different posttranslational forms of the enzyme. However, a distinctive activity underlying its tumor-promoting function is yet to be described. Here, we report that acetylation, one of such posttranslational modifications (PTMs), increases SOD2 affinity for iron, effectively changing the biochemical function of this enzyme from that of an antioxidant to a demethylase. Acetylated, iron-bound SOD2 localizes to the nucleus, promoting stem cell gene expression via removal of suppressive epigenetic marks such as H3K9me3 and H3K927me3. Particularly, H3K9me3 was specifically removed from regulatory regions upstream of Nanog and Oct-4, two pluripotency factors involved in cancer stem cell reprogramming. Phenotypically, cells expressing nucleus-targeted SOD2 (NLS-SOD2) have increased clonogenicity and metastatic potential. FeSOD2 operating as H3 demethylase requires H2O2 as substrate, which unlike cofactors of canonical demethylases (i.e., oxygen and 2-oxoglutarate), is more abundant in tumor cells than in normal tissue. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.
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影响因子：
50.3
作者：
Dravis C;Chung CY;Lytle NK;Herrera-Valdez J;Luna G;Trejo CL;Reya T;Wahl GM
通讯作者：
Wahl GM
影响因子：
7.4
作者：
Ansenberger-Fricano, Kristine;Ganini, Douglas;Mao, Mao;Chatterjee, Saurabh;Dallas, Shannon;Mason, Ronald P.;Stadler, Krisztian;Santos, Janine H.;Bonini, Marcelo G.
通讯作者：
Bonini, Marcelo G.
影响因子：
21.3
作者：
Michel BC;D'Avino AR;Cassel SH;Mashtalir N;McKenzie ZM;McBride MJ;Valencia AM;Zhou Q;Bocker M;Soares LMM;Pan J;Remillard DI;Lareau CA;Zullow HJ;Fortoul N;Gray NS;Bradner JE;Chan HM;Kadoch C
通讯作者：
Kadoch C
肺癌演化过程中高塑性细胞状态的出现。
影响因子：
50.3
作者：
Marjanovic ND;Hofree M;Chan JE;Canner D;Wu K;Trakala M;Hartmann GG;Smith OC;Kim JY;Evans KV;Hudson A;Ashenberg O;Porter CBM;Bejnood A;Subramanian A;Pitter K;Yan Y;Delorey T;Phillips DR;Shah N;Chaudhary O;Tsankov A;Hollmann T;Rekhtman N;Massion PP;Poirier JT;Mazutis L;Li R;Lee JH;Amon A;Rudin CM;Jacks T;Regev A;Tammela T
通讯作者：
Tammela T
DOI：
10.1126/science.1230593
发表时间：
2013-03-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rhee HW;Zou P;Udeshi ND;Martell JD;Mootha VK;Carr SA;Ting AY
通讯作者：
Ting AY