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Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.

Abstract：

:SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Coni S,Mancuso AB,Di Magno L,Sdruscia G,Manni S,Serrao SM,Rotili D,Spiombi E,Bufalieri F,Petroni M,Kusio-Kobialka M,De Smaele E,Ferretti E,Capalbo C,Mai A,Niewiadomski P,Screpanti I,Di Marcotullio L,Canettieri G

doi

10.1038/srep44079

subject

Has Abstract

pub_date

2017-03-09 00:00:00

pages

44079

issn

2045-2322

pii

srep44079

journal_volume

7

pub_type

杂志文章

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