Elucidating the role of the epigenetic regulator USP22 in human cancer

描述(申请人提供)：表观遗传调节因子，如多梳蛋白，控制正常干细胞和侵袭性人类癌细胞类型的关键生物学功能。最近发现了一个包括多梳基因和与多梳基因共同调控的额外基因的基因特征。这一信号的表达将肿瘤与侵袭性生长、转移和治疗耐药的肿瘤干细胞表型相鉴别。这个由11个基因组成的标记中的大多数成员都编码在人类癌症中具有明确作用的蛋白质。然而，签名成员USP22的功能仍然未知。我们最近报道，USP22是人类SAGA转录辅因子复合体的一个以前未被描述的亚基。在hSAGA中，USP22去泛素化组蛋白H_2A和H_2B，从而在转录中发挥中心作用。此外，USP22被MYC癌蛋白等激活剂招募到特定的基因，在那里它是转录所必需的。为了支持多梳/癌症干细胞信号中的功能作用，我最近通过基因枯竭表明，USP22是保护人类癌细胞免受遗传毒性应激导致的死亡所必需的。在这项提案中，我将定义USP22过度表达在侵袭性人类癌细胞中触发的确切生化事件，以保护它们免受庆大性应激和死亡。最终，我将扩展我在基因耗竭研究中的发现，以评估USP22的药理抑制是否也可以被用来选择性地诱导转化的人类细胞凋亡。

DESCRIPTION (provided by applicant): Epigenetic regulators such as the polycomb proteins control critical biological functions in both normal stem cells and aggressive human cancer cell types. A gene signature that includes polycomb genes and additional genes co-regulated with polycomb genes was recently identified. The expression of this signature identifies tumors with the cancer stem cell phenotypes of aggressive growth, metastasis and therapy resistance. Most members of this 11- gene signature encode proteins with well-defined roles in human cancer. However the function of the signature member USP22 remained unknown. We recently reported that USP22 is a previously uncharacterized subunit of the human SAGA transcriptional cofactor complex. Within hSAGA, USP22 deubiquitylates histone H2A and H2B, thereby playing a central role in transcription. Furthermore, USP22 is recruited to specific genes by activators such as the MYC oncoprotein, where it is required for transcription. In support of a functional role within the polycomb/cancer stem cell signature, I have recently shown by genetic depletion that USP22 is required for protecting human cancer cells from death induced by genotoxic stress. In this proposal, I will define the precise biochemical events that USP22 overexpression triggers in aggressive human cancer cells in order to protect them from gentoxic stress and death. Ultimately, I will extend my findings from genetic depletion studies to assess whether pharmacological inhibition of USP22 can also be exploited to selectively induce apoptosis in transformed human cells.