Histone Deacetylase 11 Is an ε- N -Myristoyllysine Hydrolase

TY - JOUR

T1 - Histone Deacetylase 11 Is an ε- N -Myristoyllysine Hydrolase

AU - Moreno-Yruela, Carlos

AU - Galleano, Iacopo

AU - Madsen, Andreas S.

AU - Olsen, Christian A.

PY - 2018/7/19

Y1 - 2018/7/19

N2 - Histone deacetylase (HDAC) enzymes regulate diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV. It is the smallest protein and has the least well understood biological function. Here, we show that HDAC11 cleaves long-chain acyl modifications on lysine side chains with remarkable efficiency. We further show that several common types of HDAC inhibitors, including the approved drugs romidepsin and vorinostat, do not inhibit this enzymatic activity. Macrocyclic hydroxamic acid-containing peptides, on the other hand, potently inhibit HDAC11 demyristoylation activity. These findings should be taken carefully into consideration in future investigations of the biological function of HDAC11 and will serve as a foundation for the development of selective chemical probes targeting HDAC11. Moreno-Yruela et al. show that histone deacetylase 11 (HDAC11) cleaves long-chain acyl modifications on lysine side chains with remarkable efficiency, and macrocyclic hydroxamic acid-containing peptides potently inhibit HDAC11 demyristoylation. These findings provide a foundation for future development of selective chemical probes targeting HDAC11.

AB - Histone deacetylase (HDAC) enzymes regulate diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV. It is the smallest protein and has the least well understood biological function. Here, we show that HDAC11 cleaves long-chain acyl modifications on lysine side chains with remarkable efficiency. We further show that several common types of HDAC inhibitors, including the approved drugs romidepsin and vorinostat, do not inhibit this enzymatic activity. Macrocyclic hydroxamic acid-containing peptides, on the other hand, potently inhibit HDAC11 demyristoylation activity. These findings should be taken carefully into consideration in future investigations of the biological function of HDAC11 and will serve as a foundation for the development of selective chemical probes targeting HDAC11. Moreno-Yruela et al. show that histone deacetylase 11 (HDAC11) cleaves long-chain acyl modifications on lysine side chains with remarkable efficiency, and macrocyclic hydroxamic acid-containing peptides potently inhibit HDAC11 demyristoylation. These findings provide a foundation for future development of selective chemical probes targeting HDAC11.

U2 - 10.1016/j.chembiol.2018.04.007

DO - 10.1016/j.chembiol.2018.04.007

M3 - Journal article

C2 - 29731425

SN - 2451-9456

VL - 25

SP - 849

EP - 856

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 7

ER -