Recently, the research group led by Professor Lei Chang at the Radiobiology Research Center of the State Key Laboratory published an article titled "Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis" in the journal Cancer Research. This study, through the construction of various gene knockout mice and multiple tumor models, elucidated the indispensable role of the Ku70-YAP-PARP1 axis in regulating and maintaining genome stability, providing new insights into the complex relationship between YAP/TAZ activity and the tumorigenesis process. The paper link: https://aacrjournals.org/cancerres/article-abstract/doi/10.1158/0008-5472.CAN-23-4034/745875/Ku70-Binding-to-YAP-Alters-PARP1-Ubiquitination-to?redirectedFrom=fulltext.
YAP/TAZ are core participants in the process of tumorigenesis, and their activity is closely related to the occurrence, progression, and poor prognosis of various tumors in multiple organs of the human body. Therefore, elucidating the specific mechanisms by which YAP regulates tumorigenesis and identifying target molecules of YAP action have become critical issues in the development of YAP-targeted anti-tumor drugs. Ku70 is a key protein in the NHEJ pathway of DNA damage repair. The research team discovered that Ku70 dynamically competes with the transcription factor TEAD4 to bind YAP, thereby influencing YAP's transcriptional activity. Under normal conditions, Ku70 binds to YAP to form a YAP/Ku70 complex, weakening the binding between YAP and TEAD4 and limiting YAP's transcriptional activity. However, the absence of Ku70 or DNA damage can promote the dissociation of YAP/Ku70, enhancing the interaction between YAP and TEAD4 and increasing YAP's transcriptional activity. In vivo, using tumor models constructed with Ku70-specific knockout mice, it was found that the absence of Ku70 could activate YAP, promoting the occurrence of colon cancer and hepatocellular carcinoma. Mechanistically, YAP activation can increase the expression of SMURF2, further promoting the ubiquitin-proteasome pathway-mediated ubiquitination and degradation of the DNA damage response protein PARP1, thereby hindering DNA damage repair and promoting genome instability and tumorigenesis (Figure 1). Finally, analysis of clinical liver cancer patient tissue samples further confirmed the link between Ku70 expression, YAP activity, PARP1 levels, and genome instability.
In summary, this study reveals the mutual regulatory mechanism between YAP and Ku70, a key regulator of DNA damage repair, emphasizing the critical role of the Ku70-YAP-PARP1 axis in maintaining genome stability. This provides new therapeutic strategies for the development of YAP-targeted anti-tumor drugs and multidisciplinary approaches to tumor diagnosis and treatment.
Figure 1： Schematic Illustration of the Mechanism of the Ku70-YAP-PARP1 Axis in Maintaining Genome Stability
Yinyin Shu, a 2021 doctoral student, Xiaoni Jin, a 2023 doctoral student, and postdoctoral researcher Mintao Ji from the School of Radiation Medicine and Protection are the co-first authors of the paper, while Professor Chang Lei from Soochow University is the corresponding author. This work was supported by the National Natural Science Foundation of China, the Fok Ying-Tong Education Foundation, the State Key Laboratory of Radiation Medicine and Radiation Protection, the Jiangsu Natural Science Foundation, and the Jiangsu Collaborative Innovation Center for Radiation Medicine.