Long noncoding RNA HOTAIR promotes the self-renewal of leukemia stem cells through epigenetic silencing of p15.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder initiated from a small subset of leukemia stem cell (LSC), which presents unrestricted self-renewal and proliferation. Long non-coding RNA HOTAIR is abundantly expressed and plays oncogenic roles in solid cancer and AML. However, whether HOTAIR regulates the self-renewal of LSC is largely unknown. Here, we reported that the expression of HOTAIR was increased in LSC than in normal hematological stem and progenitor cells (HSPCs). HOTAIR inhibition by short hairpin RNAs (shRNAs) decreased colony formation in leukemia cell lines and primary AML blasts. We then investigated the role of HOTAIR in leukemia in vivo. HOTAIR knockdown extends the survival time in U937-transplanted NSG mice. Furthermore, HOTAIR knockdown reduced infiltration of leukemic blasts, decreased frequency of LSC, and prolonged overall survival in MLL-AF9-induced murine leukemia, suggesting that HOTAIR is required for the maintenance of AML. Mechanistically, HOTAIR inhibited p15 expression through zeste homolog 2 (EZH2)-enrolled tri-methylation of Lys 27 of histone H3 (H3K27me3) in p15 promoter. In addition, p15 partially reversed the decrease of colony and proliferation induced by HOTAIR knockdown, suggesting that p15 plays an important role in the leukemogenesis by HOTAIR. In conclusion, our study suggests that HOTAIR facilitates leukemogenesis by enhancing self-renewal of LSC. HOTAIR might be a potential target for anti-LSC therapy.

• Authors: Shenmeng Gao, Bin Zhou, Haiying Li, Xingzhou Huang, Yanfei Wu, Chongyun Xing, Xiaozhuo Yu, Yanhong Ji
• Journal: Experimental hematology (Exp Hematol) Vol. 67 Pg. 32-40.e3 (11 2018) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 30172749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• CDKN2B protein, human
• Cyclin-Dependent Kinase Inhibitor p15
• HOTAIR long untranslated RNA, human
• MLL-AF9 fusion protein, mouse
• Oncogene Proteins, Fusion
• RNA, Long Noncoding
• RNA, Neoplasm
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Ezh2 protein, mouse

Topics

• Animals
• Bone Marrow Transplantation
• Cell Self Renewal (physiology)
• Cell Transformation, Neoplastic (genetics)
• Cyclin-Dependent Kinase Inhibitor p15 (antagonists & inhibitors, genetics, physiology)
• Enhancer of Zeste Homolog 2 Protein (physiology)
• Gene Expression Regulation, Leukemic
• Gene Knockdown Techniques
• Gene Silencing
• Heterografts
• Histone Code (genetics)
• Humans
• Leukemia, Myeloid, Acute (genetics, pathology)
• Mice
• Molecular Targeted Therapy
• Neoplastic Stem Cells (cytology)
• Oncogene Proteins, Fusion (genetics)
• Promoter Regions, Genetic
• RNA, Long Noncoding (physiology)
• RNA, Neoplasm (physiology)
• Tumor Stem Cell Assay
• U937 Cells