Huaier Regulates Cell Fate by the Rescue of Disrupted Transcription Control in the Hippo Signaling Pathway

Background: Among historical nature remedies in Eastern Asia, Huaier (Trametes robiniophila murr) has long been reported for its significant efficacy on longevity and health maintenance, and more importantly, on cancer. The target cancers of Huaier show the almost complete overlap with those strongly influenced by the Hippo pathway function, which is also well known as a tumor suppressor mechanism. Objective: We have initiated the present study in order to prove the hypothesis that the Hippo signaling pathway is a main molecular mechanism of Huaier effects on cancer and on multiple physiological disorders. Methods: We performed in vivo study using Drosophila flies genetically disrupted transcriptional control in the Hippo pathway with overexpressing non-phosphorylatable Yorkie (Yki:V5S168A) as a cancer model. In addition, metabolome analysis was performed using those cancer-model mutants with a comparison to healthy controls. Results: The administration of Huaier clearly resulted in the recovery of rough eye formation of the mutants, indicating the rescue of tumor suppressor mechanism disrupted by the genetically inoculated overabundant transcriptional activators. These improvements occurred in a dose-dependent manner, just as shown in clinical observations. Simultaneously, the GC/MS-based metabolome analysis revealed that Huaier uptake lead the metabolic profile of the mutant flies strongly shifted to that of the early developmental stage. Conclusion: The present study emphasizes that a broad spectrum of Huaier effects was based on the rescue of the disrupted Hippo signaling pathway control, especially on the recovery in transcriptional dysregulation. The metabolome profile shift would explain the molecular basis of the tissue recovery after a long course of Huaier treatment, by the potential to modulate the cell fate through the embryogenesis and subsequent normal specification of the cells in the damaged tissues.