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SUMMARY We investigated the transcriptional and epigenetic repression of miR-29 by Myc, HDAC3, and EZH2 in mantle cell lymphoma and other Myc-associated lymphomas. We demonstrate that miR-29 is repressed by Myc through a co-repressor complex with HDAC3 and EZH2. Myc contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces Myc via inhibition of the Myc targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the Myc-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, down-regulation of miR-29 targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a Myc-mediated miRNA repression mechanism, shed light on Myc lymphomagenesis mechanisms and reveals promising therapeutic targets for aggressive B-cell malignancies.

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Heat shock protein (hsp) 90 is an ATP-dependent molecular chaperone that maintains the active conformation of client oncoproteins in cancer cells. An isoform, hsp90A, promotes extracellular maturation of matrix metalloproteinase (MMP)-2, involved in tumor invasion and metastasis. Knockdown of histone deacetylase (HDAC) 6, which deacetylates lysine residues in hsp90, induces reversible hyperacetylation and attenuates ATP binding and chaperone function of hsp90. Here, using mass spectrometry, we identified seven lysine residues in hsp90A that are hyperacetylated after treatment of eukaryotic cells with a pan-HDAC inhibitor that also inhibits HDAC6. Depending on the specific lysine residue in the middle domain involved, although acetylation affects ATP, cochaperone, and client protein binding to hsp90A, acetylation of all seven lysines increased the binding of hsp90A to 17-allyl-amino-demethoxy geldanamycin. Notably, after treatment with the pan-HDAC inhibitor panobinostat (LBH589), the extracellular hsp90A was hyperacetylated and it bound to MMP-2, which was associated with increased in vitro tumor cell invasiveness. Treatment with antiacetylated hsp90A antibody inhibited in vitro invasion by tumor cells. Thus, reversible hyperacetylation modulates the intracellular and extracellular chaperone function of hsp90, and targeting extracellular hyperacetylated hsp90A may undermine tumor invasion and metastasis. [Cancer Res 2008;68(12):4833-42]