A Study On The Roles Of YAP In Cellular Senescence

Cellular senescence is a state of stable growth with the loss of cell proliferation, which can be induced by various stimuli such as telomere shortening, DNA damage induced by chemotherapeutic drugs or the aberrant activation of oncogenes. As cellular senescence can inhibit the cell growth, it is considered a strong barrier for carcinogenesis. However, there are an increasing number of studies showing that senescent cells can promote tumorigenesis. Specifically, accumulated senescent cells might induce cancer development in vivo, or promote the proliferation of cells around and the drug resistance via SASP (senescence-associated secretory phenotype) in solid tumor with chemotherapeutic drugs treatment. Therefore, clearing these senescent cells immediately may improve the outcome of chemotherapy treatment.Senescent cells could attract and recruit innate immune cells, including macrophages, neutrophils, and natural killer cells, to mediate the clearance of senescent tumor cells. But the immune system of aged people or patients treated with chemotherapeutic drugs is defective; senescent cells cannot be cleared efficiently by their immune system. Most senescent cells have been found to be stable in culture, which is likely due to their resistance to apoptosis. Thus, we can target their anti-apoptosis mechanisms to induce senescent cells into apoptosis, followed by clearance,In order to investigate the mechanism underlying the resistance to apoptosis of senescent cells, this study established a low-dose of doxorubicin (DOX) induced cellular senescence model. Starting with flattened and enlarged morphology the senescent cells acquired, we found YAP (Yes-associated protein), a transcription co-activator of the Hippo Pathway, was nuclear accumulated in DOX-induced senescent cells, which was probably induced by the increased cell-ECM (extracellular matrix) of senescent cells. YAP, as an oncogene hyperactivated in cancers, can promote the development of cancer. Although aberrant activation of oncogene can induce cellular senescence, overexpression of YAP and constitutively active mutant form YAPS127A failed to induce senescence in this study, so did the knockdown of YAP, which promoted more apoptosis instead. Therefore, we suggested that activation of YAP in DOX-induced senescent cells might be a mechanism to promote the survival of senescent cells, which could be exploited by cancer cells to establish resistance.Nuclear accumulated YAP had high transcription activity, which could promote the expression of its downstream target genes such as ANKRD1, CTGF and CYR61. Anti-apoptosis protein survivin is a target gene of YAP. Survivin, a member of the inhibitor of apoptosis (IAP) protein family, plays an important role in apoptosis resistance. Our study found the activation of YAP upregulated the expression of survivin in DOX-induced senescent cells; verteporfin (VP), an inhibitor of YAP, or YM155, an inhibitor of survivin could efficiently inhibit the expression of YAP target gene survivin in DOX-induced senescent cells, and induced apoptosis in senescent cells.All in all, we found that the Hippo pathway effector YAP was nuclear-localized and promoted the expression of survivin to maintain the survival of senescent cells. Inhibitors targeting YAP or survivin combined with a low dose of DOX can be used to clear senescent cells and improve the therapeutic efficacy while simultaneously reducing the cytotoxic effects.