Elucidating the role of the epigenetic regulator USP22 in human cancer

描述（由申请人提供）：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中的关键生物学功能。最近鉴定了包括多梳基因和与多梳基因共调控的额外基因的基因签名。该标记的表达鉴定具有侵袭性生长、转移和治疗抗性的癌症干细胞表型的肿瘤。这11个基因签名的大多数成员编码在人类癌症中具有明确作用的蛋白质。然而，签名成员USP 22的功能仍然未知。我们最近报道，USP 22是一个以前未知的亚基的人佐贺转录辅因子复合物。在hSAGA中，USP 22使组蛋白H2 A和H2 B去泛素化，从而在转录中发挥核心作用。此外，USP 22被激活剂如MYC癌蛋白募集到特定基因，在那里它是转录所必需的。为了支持polycomb/癌症干细胞特征中的功能作用，我最近通过基因耗竭表明，USP 22是保护人类癌细胞免受遗传毒性应激诱导的死亡所必需的。在这个提案中，我将定义USP 22过表达在侵袭性人类癌细胞中触发的精确生化事件，以保护它们免受遗传毒性应激和死亡。最终，我将从遗传耗竭研究中扩展我的发现，以评估是否也可以利用USP 22的药理学抑制来选择性地诱导转化的人类细胞的凋亡。 公共卫生相关性：USP 22是一种以前未表征的酶，作为“癌症死亡”基因签名的一部分过表达。我们已经表明，USP 22是一个关键的转录调节因子，对于保护癌细胞免受遗传毒性非常重要。 压力和细胞死亡。在这里，我将扩展我的初步观察，以确定USP 22如何保护癌细胞免于死亡，并评估是否可以利用抑制USP 22来选择性地杀死侵袭性癌细胞。

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. PUBLIC HEALTH RELEVANCE: USP22 is a previously uncharacterized enzyme that is overexpressed as part of a "death-from- cancer" gene signature. We have shown that USP22 is a critical regulator of transcription which is important for protecting cancer cells from genotoxic stress and cell death. Here I will extend my initial observations to define how USP22 protect cancer cells from death and assess whether inhibiting USP22 can be exploited to selectively kill aggressive cancer cells.