Journal of Biological Chemistry
Volume 286, Issue 38, 23 September 2011, Pages 33061-33069
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Gene Regulation
Lysine-specific Demethylase 2B (KDM2B)-let-7-Enhancer of Zester Homolog 2 (EZH2) Pathway Regulates Cell Cycle Progression and Senescence in Primary Cells

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Sustained expression of the histone demethylase, KDM2B (Ndy1/FBXL10/JHDM1B), bypasses cellular senescence in primary mouse embryonic fibroblasts (MEFs). Here, we show that KDM2B is a conserved regulator of lifespan in multiple primary cell types and defines a program in which this chromatin-modifying enzyme counteracts the senescence-associated down-regulation of the EZH2 histone methyltransferase. Senescence in MEFs epigenetically silences KDM2B and induces the tumor suppressor miRNAs let-7b and miR-101, which target EZH2. Forced expression of KDM2B promotes immortalization by silencing these miRNAs through locus-specific histone H3 K36me2 demethylation, leading to EZH2 up-regulation. Overexpression of let-7b down-regulates EZH2, induces premature senescence, and counteracts immortalization of MEFs driven by KDM2B. The KDM2B-let-7-EZH2 pathway also contributes to the proliferation of immortal Ink4a/Arf null fibroblasts suggesting that, beyond its anti-senescence role in primary cells, this histone-modifying enzyme functions more broadly in the regulation of cellular proliferation.

Cell Cycle
Epigenetics
Gene Expression
Gene Transcription
MicroRNA
KDM2B
Ezh2
Let-7
MiR-101
Senescence

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The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1–S3.

This work was supported by a National Institutes of Health, NCI/Harvard GI SPORE Grant (P50 CA127003 and R01 CA133557-01). This work was also supported by grants from the Waxman Foundation, the Andrew Warshaw Institute (to N. B.), and from the Nestora fund (to A. T.).