lncRNA ZNF649-AS1 Induces Trastuzumab Resistance by Promoting ATG5 Expression and Autophagy.

Abstract

The regulatory mechanism of long non-coding RNAs (lncRNAs) in trastuzumab resistance is not well established to date. In this research, we identified differentially expressed lncRNA and investigated its regulatory role in trastuzumab resistance of breast cancer. HiSeq sequencing and quantitative real-time PCR were performed to identify the dysregulated lncRNAs. Mass spectrometry, RNA fluorescence in situ hybridization (RNA-FISH), and immunoprecipitation assays were performed to identify the direct interactions between ZNF649-AS1 and other associated targets, such as polypyrimidine tract binding protein 1 (PTBP1) and autophagy related 5 (ATG5). Our results showed that ZNF649-AS1 was more highly expressed in trastuzumab-resistant cells compared to sensitive cells. Increased expression of ZNF649-AS1 was associated with a poorer response and shorter survival time of breast cancer patients. ZNF649-AS1 was upregulated by H3K27ac modification at the presence of trastuzumab treatment, and knockdown of ZNF649-AS1 reversed trastuzumab resistance via modulating ATG5 expression and autophagy. Mechanically, ZNF649-AS1 was associated with PTBP1 protein, which further promoted the transcription activity of the ATG5 gene. In conclusion, we demonstrated that H3K27ac modification-induced upregulation of ZNF649-AS1 could cause autophagy and trastuzumab resistance through associating with PTBP1 and promoting ATG5 transcription.

• Authors: Mingli Han, Xueke Qian, Hui Cao, Fang Wang, Xiangke Li, Na Han, Xue Yang, Yunqing Yang, Dongwei Dou, Jianguo Hu, Wei Wang, Jing Han, Fan Zhang, Huaying Dong
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 28 Issue 11 Pg. 2488-2502 (11 04 2020) ISSN: 1525-0024 [Electronic] United States
• PMID: 32735773 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• ATG5 protein, human
• Antineoplastic Agents, Immunological
• Autophagy-Related Protein 5
• RNA, Long Noncoding
• Trastuzumab

Topics

• Antineoplastic Agents, Immunological (pharmacology)
• Autophagy (genetics)
• Autophagy-Related Protein 5 (genetics)
• Cell Line, Tumor
• Cell Proliferation
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• RNA, Long Noncoding (genetics)
• Trastuzumab (pharmacology)