Identification of deubiquitinase targets of isothiocyanates using SILAC-assisted quantitative mass spectrometry.
Identification of deubiquitinase targets of isothiocyanates using SILAC-assisted quantitative mass spectrometry.
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DOI：
10.18632/oncotarget.17261
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Hedstrom L
中科院分区：
文献类型：
--
作者：
Lawson AP;Bak DW;Shannon DA;Long MJC;Vijaykumar T;Yu R;Oualid FE;Weerapana E;Hedstrom L
十字花科蔬菜，如西兰花和羽衣甘蓝，有充分的化学预防和抗癌作用，这归因于异硫氰酸酯（ITCs）的存在。ITC调节许多致癌蛋白的水平，但ITC作用的分子机制尚不清楚。我们以前报道过异硫氰酸苯乙酯（PEITC）抑制两种去泛素酶（DUBs）， USP9x和UCH37。DUB调节许多细胞过程，DUB失调与人类疾病的发病机制有关，包括癌症、神经变性和炎症。利用SILAC辅助定量质谱技术，我们鉴定出9个新的petc - dub靶点：USP1、USP3、USP10、USP11、USP16、USP22、USP40、USP48和VCPIP1。其中7种petc敏感dub在DNA修复或染色质重塑中具有公认的作用。PEITC既抑制USP1，又增加其泛素化和降解，从而通过两种机制降低USP1的活性。USP1活性的丧失增加了单泛素化DNA钳夹PCNA的水平，损害了DNA修复。USP1的抑制/降解和单泛素化PCNA的增加都是PEITC的新活性，这可以解释之前公认的ITCs增强癌细胞对顺铂治疗敏感性的能力。我们的工作还表明，PEITC降低了单泛素组蛋白H2A和H2B。了解ITCs的作用机制有助于其作为治疗剂的使用。
Cruciferous vegetables such as broccoli and kale have well documented chemopreventative and anticancer effects that are attributed to the presence of isothiocyanates (ITCs). ITCs modulate the levels of many oncogenic proteins, but the molecular mechanisms of ITC action are not understood. We previously reported that phenethyl isothiocyanate (PEITC) inhibits two deubiquitinases (DUBs), USP9x and UCH37. DUBs regulate many cellular processes and DUB dysregulation is linked to the pathogenesis of human diseases including cancer, neurodegeneration, and inflammation. Using SILAC assisted quantitative mass spectrometry, here we identify 9 new PEITC-DUB targets: USP1, USP3, USP10, USP11, USP16, USP22, USP40, USP48 and VCPIP1. Seven of these PEITC-sensitive DUBs have well-recognized roles in DNA repair or chromatin remodeling. PEITC both inhibits USP1 and increases its ubiquitination and degradation, thus decreasing USP1 activity by two mechanisms. The loss of USP1 activity increases the level of mono-ubiquitinated DNA clamp PCNA, impairing DNA repair. Both the inhibition/degradation of USP1 and the increase in mono-ubiquitinated PCNA are new activities for PEITC that can explain the previously recognized ability of ITCs to enhance cancer cell sensitivity to cisplatin treatment. Our work also demonstrates that PEITC reduces the mono-ubiquityl histones H2A and H2B. Understanding the mechanism of action of ITCs should facilitate their use as therapeutic agents.
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影响因子：
4.1
作者：
Boyanapalli SS;Paredes-Gonzalez X;Fuentes F;Zhang C;Guo Y;Pung D;Saw CL;Kong AN
通讯作者：
Kong AN
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--
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影响因子：
3.2
作者：
Andreopoulou E;Schweber SJ;Sparano JA;McDaid HM
通讯作者：
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影响因子：
44.1
作者：
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通讯作者：
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