RESUMO
Yes-associated protein (YAP) is a central player in cancer development, with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/transcriptional coactivator with PDZ-binding motif (TAZ) and the DNA damage response. Here, we investigated the mechanistic underpinnings of the cross-talk between DNA damage repair and YAP activity. Ku70, a key component of the nonhomologous end joining pathway to repair DNA damage, engaged in a dynamic competition with TEAD4 for binding to YAP, limiting the transcriptional activity of YAP. Depletion of Ku70 enhanced interaction between YAP and TEAD4 and boosted YAP transcriptional capacity. Consequently, Ku70 loss enhanced tumorigenesis in colon cancer and hepatocellular carcinoma (HCC) in vivo. YAP impeded DNA damage repair and elevated genome instability by inducing PARP1 degradation through the SMURF2-mediated ubiquitin-proteasome pathway. Analysis of samples from patients with HCC substantiated the link between Ku70 expression, YAP activity, PARP1 levels, and genome instability. In conclusion, this research provides insight into the mechanistic interactions between YAP and key regulators of DNA damage repair, highlighting the role of a Ku70-YAP-PARP1 axis in preserving genome stability. Significance: Increased yes-associated protein transcriptional activity stimulated by loss of Ku70 induces PARP1 degradation by upregulating SMURF2 to inhibit DNA damage, driving genome instability and tumorigenesis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ligação a DNA , Instabilidade Genômica , Autoantígeno Ku , Poli(ADP-Ribose) Polimerase-1 , Fatores de Transcrição , Ubiquitinação , Proteínas de Sinalização YAP , Humanos , Autoantígeno Ku/metabolismo , Autoantígeno Ku/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Sinalização YAP/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Animais , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Camundongos , Carcinogênese/genética , Carcinogênese/metabolismo , Fatores de Transcrição de Domínio TEA/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Dano ao DNA , Reparo do DNA , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Camundongos NusRESUMO
Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.
Assuntos
Adrenomedulina , Disfunção Erétil , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Animais , Humanos , Masculino , Camundongos , Ratos , Adrenomedulina/fisiologia , Disfunção Erétil/genética , Ereção Peniana/fisiologia , Pênis , Estudos Retrospectivos , Proteínas de Sinalização YAP/fisiologia , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/fisiologiaRESUMO
Hadron therapy with protons and carbon ions is widely attracting interest as a potential competitor of conventional photon radiotherapy. Exquisite dose distribution of charged particles allows for a higher local control of the tumor and lower probability of damage to nearby healthy tissues. Heavy ions have presumed biological advantages rising from their high-linear energy transfer (LET) characteristics, including greater cell-killing effectiveness and reduced heterogeneity dependence of radiation response. Although these advantages are clear and supported by data, only 18.0% of proton and carbon ion radiotherapy (CIRT) facilities in Europe are treating breast cancers. This review summarizes the physical and radiobiological properties of charged particles, clinical use of particle beam for breast cancer, and suggested approaches to overcome technical and financial challenges.