The BTB-zinc finger transcription factor Abrupt acts as an epithelial oncogene in Drosophila through maintaining a progenitor-like cell state

The capacity of tumor cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled, and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumors in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumor formation in cooperation with the loss of Scribbled. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scribbled promotes cooperation with Abrupt through impaired Hippo signaling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK signaling, which is required for tumor cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumors in Drosophila can be characterised by the maintenance of a progenitor-like state. ChIP-Seq of Abrupt, ChIP-Seq of Abrupt (scrib-), Input, Input (scrib-)

肿瘤细胞维持持续过度增殖潜能的能力，与劫持正常自我更新通路密切相关。本研究以果蝇上皮癌症模型为实验体系，开展了一项过表达筛选，以寻找可协同缺失上皮顶-基底细胞极性调节因子scribbled（Scrib）的致癌基因，并成功鉴定出细胞命运调节因子Abrupt——一种BTB-锌指结构蛋白。仅单独过表达Abrupt不足以引发细胞转化，但当其与scribbled功能缺失协同作用时，Abrupt可诱导果蝇眼/触角盘中形成大规模肿瘤。已知类固醇激素受体辅激活因子Taiman（SRC3/AIB1）可与Abrupt结合，且Taiman过表达同样可协同scribbled缺失驱动肿瘤发生。表达芯片与染色质免疫沉淀测序（ChIP-Seq）结果显示，Abrupt过表达会抑制大量基因的转录，其中包括类固醇激素应答基因与多种细胞命运调节因子，从而使细胞维持在上皮祖细胞样状态。该上皮祖细胞样状态具有如下特征：在眼盘中无法表达保守的Eyes absent/Dachshund调控复合物，而在触角盘中则无法表达定义附肢沿Distalless（Dll）下游近-远轴时序分化的细胞命运调节因子。scribbled缺失可通过两条信号通路与Abrupt发挥协同增殖作用：其一为受损的Hippo信号通路，其是与Abrupt协同诱导细胞过度增殖所必需且充分的条件；其二为JNK信号通路，其仅为肿瘤细胞迁移/侵袭所必需，并不参与细胞过度增殖过程。综上，本研究鉴定出一种新型协同致癌基因，其哺乳动物同源家族成员同样属于已报道的致癌基因；同时证实果蝇上皮肿瘤可通过维持祖细胞样状态进行分子表型表征。本研究配套的测序数据集包括：Abrupt的ChIP-Seq、Abrupt（scrib-）的ChIP-Seq、Input对照、Input（scrib-）对照。