Histone deacetylase 1 plays a predominant pro-oncogenic role in Eμ-myc driven B cell lymphoma.

Vincent Pillonel,Gabriele Matthias,Alexandar Tzankov,Patrick Matthias,Chun Cao,Teppei Yamaguchi,Nina Reichert,Marinus R Heideman

doi:10.1038/srep37772

Abstract

The two histone deacetylases (Hdacs), Hdac1 and Hdac2, are erasers of acetylation marks on histone tails, and are important regulators of gene expression that were shown to play important roles in hematological malignancies. However, several recent studies reported opposing tumor-suppressive or tumor-promoting roles for Hdac1 and Hdac2. Here, we investigated the functional role of Hdac1 and Hdac2 using the Eμ-myc mouse model of B cell lymphoma. We demonstrate that Hdac1 and Hdac2 have a pro-oncogenic role in both Eμ-myc tumorigenesis and tumor maintenance. Hdac1 and Hdac2 promote tumorigenesis in a gene dose-dependent manner, with a predominant function of Hdac1. Our data show that Hdac1 and Hdac2 impact on Eμ-myc B cell proliferation and apoptosis and suggest that a critical level of Hdac activity may be required for Eμ-myc tumorigenesis and proper B cell development. This provides the rationale for utilization of selective Hdac1 and Hdac2 inhibitors in the treatment of hematological malignancies.

Highlights

Histone deacetylases (Hdacs) belong to a family of 18 enzymes that remove acetylation marks on lysine residues of histone and non-histone proteins[1]
Previous studies reported that T cell-32,33 and epidermal cell-34 specific ablation of Hdac[1] and Hdac[2] alleles unexpectedly leads to spontaneous tumor formation
Our results indicate that Hdac[1] and Hdac[2] do not have a tumor suppressor function in B cells

Summary

Introduction

Histone deacetylases (Hdacs) belong to a family of 18 enzymes that remove acetylation marks on lysine residues of histone and non-histone proteins[1]. Four pan-HDACis, (targeting class I and/or class II HDACs12) are approved for the treatment of T cell lymphoma and multiple myeloma[13,14,15,16] and several others are in clinical trials for various cancers, including B cell malignancies (reviewed by[9]). It is unclear which HDAC isoforms are crucial for tumor cell growth and/or survival, and whether selective HDAC inhibition might have comparable therapeutic benefit with less toxicity compared with broad-spectrum HDACis[2,17]. This study reveals that Hdac[1] and Hdac[2] have a gene dose-dependent pro-oncogenic role in Eμ-myc tumorigenesis, with a predominant role of Hdac[1]

Methods

Results

Conclusion