Department of Pathology, University of Iowa, Iowa City, IA, USA; Cancer Biology Graduate Program, University of Iowa, Iowa City, IA, USA.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Trends Cancer. 2022 Dec;8(12):1033-1045. doi: 10.1016/j.trecan.2022.08.002. Epub 2022 Sep 9.
The Hippo pathway is dysregulated in many different cancers, but point mutations in the pathway are rare. Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) fusion proteins have emerged in almost all major cancer types and represent the most common genetic mechanism by which the two transcriptional co-activators are activated. Given that the N termini of TAZ or YAP are fused to the C terminus of another transcriptional regulator, the resultant fusion proteins hyperactivate a TEAD transcription factor-based transcriptome. Recent advances show that the C-terminal fusion partners confer oncogenic properties to TAZ/YAP fusion proteins by recruiting epigenetic modifiers that promote a hybrid TEAD-based transcriptome. Elucidating these cooperating epigenetic complexes represents a strategy to identify new therapeutic approaches for a pathway that has been recalcitrant to medical therapy.
Hippo 通路在许多不同的癌症中失调，但该通路的点突变很少见。PDZ 结合基序转录共激活因子（TAZ）和 Yes 相关蛋白（YAP）融合蛋白几乎出现在所有主要癌症类型中，是这两种转录共激活因子激活的最常见遗传机制。鉴于 TAZ 或 YAP 的 N 端融合到另一个转录调节剂的 C 端，所得融合蛋白会过度激活基于 TEAD 转录因子的转录组。最近的进展表明，C 端融合伙伴通过招募表观遗传修饰因子来赋予 TAZ/YAP 融合蛋白致癌特性，从而促进基于混合 TEAD 的转录组。阐明这些协同的表观遗传复合物是识别该通路的新治疗方法的一种策略，该通路一直对医学治疗有抵抗力。
