Dysfunction of nucleus accumbens-1 activates cellular senescence and inhibits tumor cell proliferation and oncogenesis.
Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction of NAC1 induces senescence and inhibits its oncogenic potential. We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of γ-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1-/- cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivo when compared with NAC1+/+ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by ΔNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of ΔNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment.
Department of Pharmacology, College of Pharmaceutical Sciences, Cyrus Tang Hematology Center, Soochow University, Suzhou, JiangSu, China.
Yi
Y
Zhang
Yan
Y
Cheng
Xingcong
X
Ren
Tsukasa
T
Hori
Kathryn J
KJ
Huber-Keener
Li
L
Zhang
Kai Lee
KL
Yap
David
D
Liu
Lisa
L
Shantz
Zheng-Hong
ZH
Qin
Suping
S
Zhang
Jianrong
J
Wang
Hong-Gang
HG
Wang
Ie-Ming
IeM
Shih
Jin-Ming
JM
Yang
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016922:Cellular Senescence / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
C516477:NACC1 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D016283:Proto-Oncogene Proteins p21(ras)