title: Nuclear accumulation of Yes-Associated Protein (YAP) maintains the survival of doxorubicin-induced senescent cells by promoting survivin expression.
abstract: Although chemotherapeutic drugs can induce senescence to prohibit further division of tumor cells, senescence could also promote tumorigenesis mainly through a senescence-associated secretory phenotype. Therefore, senescent tumor cells should be eliminated immediately to prevent drug resistance and recurrence. Here, we used a doxorubicin-induced senescence model to explore the mechanism underlying the survival of therapy-induced senescent cells. After low-dose doxorubicin treatment, tumor cells turned on a senescence program and became large and flattened, increasing their contact area with the extracellular matrix (ECM). Furthermore, Yes-associated protein (YAP) accumulated in the nucleus and YAP activity was increased in doxorubicin-induced senescent cells. Knockdown of YAP increased the sensitivity of cells to low-dose doxorubicin treatment, causing apoptosis rather than senescence. Moreover, the anti-apoptotic gene survivin, a YAP target gene, was overexpressed in senescent cells. Inhibition of survivin could lead to selective elimination of senescent cells through apoptosis. Our study indicates that nuclear accumulation of YAP could promote the survival of senescent cells by increasing survivin expression. Therefore, targeting YAP or survivin might be a new strategy for clearing senescent cancer cells during drug treatment.
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Ma
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Shuren
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Weina
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, No.17, 3rd Section of People's South Road, Chengdu 610041, China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China. Electronic address: drhxzhu@cicams.ac.cn.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, No.17, 3rd Section of People's South Road, Chengdu 610041, China. Electronic address: xuningzhi@cicams.ac.cn.
authors.forename: Ningzhi
authors.initials: N
authors.lastname: Xu
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival; D016922:Cellular Senescence; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D000077022:Survivin; D014157:Transcription Factors; D015533:Transcriptional Activation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D000077022:Survivin; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D004317:Doxorubicin
keywords: Doxorubicin; Senescence; Survivin; YAP