OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis.
OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis.
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DOI：
10.1002/advs.202004504
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
You H
中科院分区：
文献类型：
--
作者：
Gong Z;Li A;Ding J;Li Q;Zhang L;Li Y;Meng Z;Chen F;Huang J;Zhou D;Hu R;Ye J;Liu W;You H
OTUD 7 B的基因组扩增在人类癌症中经常发现。但其在肿瘤发生中的作用知之甚少。已知赖氨酸特异性脱甲基酶1（LSD 1）通过与CoREST/组蛋白脱乙酰酶（HDAC）形成辅阻遏物复合物来执行表观遗传调节。然而，细胞维持LSD 1/CoREST复合物完整性的分子机制尚不清楚。在这里，据报道LSD 1蛋白经历K63连接的多聚泛素化。OTUD 7 B负责LSD 1在K226/277残基处的去泛素化，导致LSD 1结合伴侣特异性和细胞稳态的动态控制。OTUD 7 B缺陷增加了LSD 1的K63连接的泛素化，这破坏了LSD 1/CoREST复合物的形成，并靶向LSD 1进行p62介导的蛋白水解。因此，OTUD 7 B缺陷会损害全基因组LSD 1的占有率，并增强H3 K4/H3 K9的甲基化，从而深刻影响全局基因表达并消除乳腺癌转移。此外，OTUD 7 B的生理波动调节细胞周期依赖性LSD 1振荡，确保G1/S转换。OTUD 7 B和LSD 1蛋白在高级别或转移性人乳腺癌中过度表达，而任一蛋白的失调均与不良生存和转移相关。因此，OTUD 7 B在维持LSD 1/CoREST辅阻遏物复合物的完整性、LSD 1转换和乳腺癌转移中发挥独特的伴侣转换作用。OTUD 7 B催化赖氨酸特异性脱甲基酶1（LSD 1）的K63连接的去泛素化，这是一个在调节细胞内稳态和LSD 1结合伴侣特异性方面至关重要的过程。OTUD 7 B通过调节全基因组LSD 1分布和H3 K4 me 2富集来调节LSD 1依赖性转录组。这两种蛋白质在高级别或转移性人乳腺癌中过量表达，突出了OTUD 7 B信号转导失调在通过LSD 1驱动乳腺癌转移中的独特作用。
Genomic amplification of OTUD7B is frequently found across human cancers. But its role in tumorigenesis is poorly understood. Lysine‐specific demethylase 1 (LSD1) is known to execute epigenetic regulation by forming corepressor complex with CoREST/histone deacetylases (HDACs). However, the molecular mechanisms by which cells maintain LSD1/CoREST complex integrity are unknown. Here, it is reported that LSD1 protein undergoes K63‐linked polyubiquitination. OTUD7B is responsible for LSD1 deubiquitination at K226/277 residues, resulting in dynamic control of LSD1 binding partner specificity and cellular homeostasis. OTUD7B deficiency increases K63‐linked ubiquitination of LSD1, which disrupts LSD1/CoREST complex formation and targets LSD1 for p62‐mediated proteolysis. Consequently, OTUD7B deficiency impairs genome‐wide LSD1 occupancy and enhances the methylation of H3K4/H3K9, therefore profoundly impacting global gene expression and abrogating breast cancer metastasis. Moreover, physiological fluctuation of OTUD7B modulates cell cycle‐dependent LSD1 oscillation, ensuring the G1/S transition. Both OTUD7B and LSD1 proteins are overpresented in high‐grade or metastatic human breast cancer, while dysregulation of either protein is associated with poor survival and metastasis. Thus, OTUD7B plays a unique partner‐switching role in maintaining the integrity of LSD1/CoREST corepressor complex, LSD1 turnover, and breast cancer metastasis. OTUD7B catalyzes K63‐linked deubiquitination of lysine‐specific demethylase 1 (LSD1), a process that is pivotal in regulating cellular homeostasis and the binding partner specificities of LSD1. OTUD7B regulates LSD1‐dependent transcriptome via modulating genome‐wide LSD1 distribution and H3K4me2 enrichment. Both proteins are overpresented in high‐grade or metastatic human breast cancer, highlighting a unique role of dysregulated OTUD7B signaling in driving breast cancer metastasis via LSD1.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1084/jem.20151426
发表时间：
2016-03-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hu H;Wang H;Xiao Y;Jin J;Chang JH;Zou Q;Xie X;Cheng X;Sun SC
通讯作者：
Sun SC
影响因子：
16.6
作者：
Kalin JH;Wu M;Gomez AV;Song Y;Das J;Hayward D;Adejola N;Wu M;Panova I;Chung HJ;Kim E;Roberts HJ;Roberts JM;Prusevich P;Jeliazkov JR;Roy Burman SS;Fairall L;Milano C;Eroglu A;Proby CM;Dinkova-Kostova AT;Hancock WW;Gray JJ;Bradner JE;Valente S;Mai A;Anders NM;Rudek MA;Hu Y;Ryu B;Schwabe JWR;Mattevi A;Alani RM;Cole PA
通讯作者：
Cole PA
影响因子：
4.7
作者：
Babu, JR;Geetha, T;Wooten, MW
通讯作者：
Wooten, MW
影响因子：
64.5
作者：
KING, RW;PETERS, JM;KIRSCHNER, MW
通讯作者：
KIRSCHNER, MW