The long noncoding RNA HOTAIRM1 controlled by AML1 enhances glucocorticoid resistance by activating RHOA/ROCK1 pathway through suppressing ARHGAP18.

Abstract

Acquired resistance to glucocorticoids (GCs) is an obstacle to the effective treatment of leukemia, but the molecular mechanisms of steroid insensitivity have not been fully elucidated. In this study, we established an acquired GC-resistant leukemia cell model and found a long noncoding RNA, HOTAIRM1, was overexpressed in the resistant cells by transcriptional profiling, and was higher expressed in patients with poor prognosis. The whole-genome-binding sites of HOTAIRM1 were determined by ChIRP-seq (chromatin isolation by RNA purification combined with sequencing) analysis. Further study determined that HOTAIRM1 bound to the transcriptional inhibitory region of ARHGAP18 and repressed the expression of ARHGAP18, which led to the increase of RHOA/ROCK1 signaling pathway and promoted GC resistance through antiapoptosis of leukemia cells. The inhibition of ROCK1 in GC-resistant cells could restore GCs responsiveness. In addition, HOTAIRM1 could also act as a protein sequester to prevent transcription factor AML1(acute myeloid leukemia 1) from binding to the regulatory region of ARHGAP18 by interacting with AML1. At last, we also proved AML1 could directly activate the expression of HOTAIRM1 through binding to the promoter of HOTAIRM1, which enriched the knowledge on the regulation of lncRNAs. This study revealed epigenetic causes of glucocorticoid resistance from the perspective of lncRNA, and laid a foundation for the optimization of glucocorticoid-based leukemia treatment strategy in clinic.

• Authors: Liang Liang, Wenbin Gu, Meng Li, Ran Gao, Xin Zhang, Chongye Guo, Shuangli Mi
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 7 Pg. 702 (07 14 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34262023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• ARHGAP18 protein, human
• Antineoplastic Agents
• Core Binding Factor Alpha 2 Subunit
• GTPase-Activating Proteins
• Glucocorticoids
• MicroRNAs
• RUNX1 protein, human
• long non-coding RNA HOTAIRM1, human
• RHOA protein, human
• Dexamethasone
• ROCK1 protein, human
• rho-Associated Kinases
• rhoA GTP-Binding Protein

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Cell Line, Tumor
• Core Binding Factor Alpha 2 Subunit (genetics, metabolism)
• Dexamethasone (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• GTPase-Activating Proteins (genetics, metabolism)
• Gene Expression Regulation, Leukemic
• Glucocorticoids (pharmacology)
• HEK293 Cells
• Humans
• Leukemia (drug therapy, enzymology, genetics, pathology)
• MicroRNAs (genetics, metabolism)
• Protein Binding
• Signal Transduction
• rho-Associated Kinases (genetics, metabolism)
• rhoA GTP-Binding Protein (genetics, metabolism)