Dual Role of EZH2 in Cutaneous Anaplastic Large Cell Lymphoma: Promoting Tumor Cell Survival and Regulating Tumor Microenvironment.

Abstract

Primary cutaneous anaplastic T-cell lymphoma, characterized by the CD30+ anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma. Little is known about the mechanisms of disease progression. Here we report that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 that mediates histone H3 lysine 27 trimethylation, is overexpressed in CD30+ anaplastic cells in primary cutaneous anaplastic T-cell lymphoma and large-cell transformed cutaneous T-cell lymphoma. Silencing EZH2 or inhibiting its histone methyltransferase activity conferred increased apoptosis and G1 cell-cycle arrest in primary cutaneous anaplastic T-cell lymphoma cells in vitro and a xenograft model in vivo. This was mediated by the de-repression of thioredoxin-interacting protein, a major redox control molecule, and consequent formation of reactive oxygen species. Silencing thioredoxin-interacting protein abrogated reactive oxygen species accumulation in EZH2 suppressed cells and rescued cell growth disadvantage. Moreover, EZH2 suppression de-repressed C-X-C motif chemokine ligand 10 and facilitated the recruitment of effector CD4+ and CD8+ T cells into the tumor microenvironment via a C-X-C motif chemokine ligand 10/receptor 3 interaction. These results demonstrate a dual role for polycomb repressive complex 2-mediated epigenetic silencing in tumor progression and antitumor immunity in primary cutaneous anaplastic T-cell lymphoma, and provide a rationale for the pharmacologic inhibition of EZH2 activity in large-cell transformed cutaneous T-cell lymphoma.

• Authors: Shengguo Yi, Jingru Sun, Lei Qiu, Wenjing Fu, Anqi Wang, Xiaoqing Liu, Yong Yang, Marshall E Kadin, Ping Tu, Yang Wang
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 138 Issue 5 Pg. 1126-1136 (05 2018) ISSN: 1523-1747 [Electronic] United States
• PMID: 29248547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Chemokine CXCL10
• Reactive Oxygen Species
• Receptors, CXCR3
• TXNIP protein, human
• Histone Methyltransferases
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• Animals
• Carrier Proteins (genetics, physiology)
• Cell Survival
• Chemokine CXCL10 (genetics, physiology)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, physiology)
• Histone Methyltransferases (metabolism)
• Humans
• Lymphoma, Large-Cell, Anaplastic (drug therapy, etiology, pathology)
• Mice
• Reactive Oxygen Species (metabolism)
• Receptors, CXCR3 (physiology)
• Skin Neoplasms (drug therapy, etiology, pathology)
• Tumor Microenvironment