Abstract
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.
©2012 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Growth Processes / physiology
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology*
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Cellular Senescence / physiology
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Female
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HeLa Cells
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Humans
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Mice
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Mice, Nude
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology*
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Proto-Oncogene Proteins p21(ras) / metabolism
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Repressor Proteins / deficiency
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription Factors / metabolism
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Transfection
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / metabolism
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / pathology*
Substances
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NACC1 protein, human
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Neoplasm Proteins
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RNA, Small Interfering
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Repressor Proteins
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TP53 protein, human
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TP63 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Proto-Oncogene Proteins p21(ras)