Journal
FASEB JOURNAL
Volume 29, Issue 5, Pages 2070-2080Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-257931
Keywords
organoids; histone deacetylase inhibitor; histone deacetylase; MS-275
Categories
Funding
- Dutch Cancer Society [KWF-2007-3978, KWF NKI 2009-4511, UvA2009-4416, UvA2012-5735]
- Netherlands Organization for Scientific Research [NWO-VIDI 864.07.008]
- Netherlands Organization for Scientific Research (Gravitation
- Zwaartekracht)
- Maag, Lever en Darm Stichting (MLDS) [FP13-07]
- Alpe d'Huzes/Dutch Cancer Society (CONNECTION)
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Histone deacetylases (HDACs) are posttranslational modifiers that deacetylate proteins. Despite their crucial role in numerous biological processes, the use of broad-range HDAC inhibitors (HDACi), has shown clinical efficacy. However, undesired side effects highlight the necessity to better understand the biology of different HDACs and target the relevant HDACs. Using a novel mouse model, in which HDAC1 and HDAC2 can be simultaneously deleted in the intestine of adult mice, we show that the simultaneous deletion of HDAC1 and HDAC2 leads to a rapid loss of intestinal homeostasis. Importantly, this deletion cannot be sustained, and 8 days after initial ablation, stem cells that have escaped HDAC1 or HDAC2 deletion swiftly repopulate the intestinal lining. In vitro ablation of HDAC1 and HDAC2 using intestinal organoid cultures resulted in a down-regulation of multiple intestinal stem cell markers and functional loss of clonogenic capacity. Importantly, treatment of wild-type organoids with class I-specific HDACi MS-275 also induced a similar loss of stemness, providing a possible rationale for the gastrointestinal side effects often observed in HDACi-treated patients. In conclusion, these data show that HDAC1 and HDAC2 have a redundant function and are essential to maintain intestinal homeostasis.
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