期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 3, 页码 E328-E337出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1520469113
关键词
nuclear corepressor 1; thyroid hormone receptor; tumor growth; metastasis; transcription
资金
- Ministerio de Economia y Competitividad [BFU2011-28058, BFU2014-53610-P]
- Comunidad de Madrid [S2011/BMD-2328]
- Instituto de Salud Carlos III [RD12/0036/0030, PI080971, RD12 0036/0064, PI12/00386]
- Asociacion Espanola Contra el Cancer
- European Fund for Economic and Regional Development
Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor beta 1 (TR beta) appears to be associated with cancer onset and progression. We found that expression of TR beta increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TR beta. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.
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