Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd–Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd–Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick (drm), which functions as a pseudosubstrate by displacing Bowl from the Hyd–Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd–Lin–Bowl pathway by directly repressing the transcription of the micropeptide drm. Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis.

中文翻译：

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Hyd/UBR5 定义了一种肿瘤抑制途径，将 Polycomb 抑制复合物与组织生长控制和肿瘤发生中受调节的蛋白质降解联系起来


肿瘤抑制基因在正常组织稳态中发挥着关键作用，它们的失调是包括癌症在内的人类疾病的基础。除了人类遗传学之外，果蝇等模式生物在发现肿瘤抑制途径方面也发挥了重要作用，这些途径随后被证明与人类癌症高度相关。在这里，我们展示了增生性盘 (Hyd) 和线 (Lin) 定义了一种强制性肿瘤，其中，增生性盘 (Hyd) 是在果蝇中基因分离的第一个肿瘤抑制因子，它编码一种具有迄今未知底物的 E3 泛素连接酶，而线 (Lin) 则以其在胚胎分割中的作用而闻名。抑制蛋白复合物 (Hyd-Lin) 靶向含锌指的癌蛋白 Bowl，进行泛素介导的降解，Lin 作为底物适配器将 Bowl 募集到 Hyd 进行泛素化。有趣的是，Hyd-Lin 复合物的活性直接被另一个锌指基因鼓槌( drm ) 编码的微肽所抑制，该基因作为假底物通过从 Hyd-Lin 复合物中取代 Bowl 来发挥作用，从而稳定 Bowl。我们通过直接抑制微肽drm的转录，进一步确定表观遗传调节因子 Polycomb 抑制复合物 1 (PRC1) 是 Hyd-Lin-Bowl 通路的关键上游调节因子。与这些分子研究一致，我们表明 Hyd、Lin 或 PRC1 的基因失活导致体内碗依赖性增生组织过度生长。 我们还提供证据表明 Hyd（UBR5，已知在各种人类癌症中反复失调）、Lin (LINS1) 和 Bowl (OSR1/2) 的哺乳动物同源物构成人类细胞中类似的蛋白质降解途径，并且 OSR2 促进前列腺癌肿瘤发生。总而言之，这些发现定义了一种以前未被认识的肿瘤抑制途径，该途径将表观遗传程序与组织生长控制和肿瘤发生中的受调节蛋白质降解联系起来。