SP1-induced lncRNA AGAP2-AS1 expression promotes chemoresistance of breast cancer by epigenetic regulation of MyD88
Authors: Shaowei Mo
Ru Chen
Jing Han
Wei Wang
Kejian Zou
Huaying Dong
Jianguo Hu
Fan Zhang
Journal: Journal of Experimental & Clinical Cancer Research (2018)
Discipline: CLINICAL MEDICINE
Keywords: Breast cancer; H3K27 acetylation; MyD88; SP1; Trastuzumab
Affiliations: Department of General Surgery, Hainan General Hospital, Jinan University, No.19 Xiu Hua Road, Xiuying District, Haikou city, 570311, Hainan Province, China. ., Department of General Surgery, Hainan General Hospital, Jinan University, No.19 Xiu Hua Road, Xiuying District, Haikou city, 570311, Hainan Province, China., Department of Science and Education, Hainan Maternal and Child health hospital, Haikou, 570206, Hainan, China., Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.

Abstract:  Background: Resistance to trastuzumab has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Cell behavior can be modulated by long non-coding RNAs (lncRNAs), but the contribution of lncRNAs in trastuzumab resistance to breast cancer is largely unknown. To this end, the involvement and regulatory function of lncRNA AGAP2-AS1 in human breast cancer are yet to be investigated. Methods: Trastuzumab-resistant SKBR-3 and BT474 cells were obtained by continuous culture with 5 mg/mL trastuzumab for 6 months. RT-qPCR assay was used to determine the expression of AGAP2-AS1 in tissues and cells. RNA fluorescence in situ hybridization was used to investigate the subcellular location of AGAP2-AS1 in breast cancer cells. Bioinformatic analysis, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), western blotting, and immunofluorescence were carried out to verify the regulatory interaction of AGAP2-AS1, CREB-binding protein (CBP), and MyD88. In addition, a series of in vitro assays and a xenograft tumor model were used to analyze the functions of AGAP2-AS1 in breast cancer cells. Results: AGAP2-AS1 was upregulated and transcriptionally induced by SP1 in breast cancer. Overexpression of AGAP2-AS1 promoted cell growth, suppressed apoptosis, and caused trastuzumab resistance, whereas knockdown of AGAP2-AS1 showed an opposite effect. MyD88 was identified as a downstream target of AGAP2-AS1 and mediated the AGAP2-AS1-induced oncogenic effects. Mechanistically, the RIP assay revealed that AGAP2-AS1 could bind to CBP, a transcriptional co-activator. ChIP assays showed that AGAP2-AS1-bound CBP increased the enrichment of H3K27ac at the promoter region of MyD88, thus resulting in the upregulation of MyD88. Gain- and loss-of-function assays confirmed that the NF-κB pathway was activated by MyD88 and AGAP2-AS1. Furthermore, high AGAP2-AS1 expression was associated with poor clinical response to trastuzumab therapy in breast cancer patients. Conclusion: AGAP2-AS1 could promote breast cancer growth and trastuzumab resistance by activating the NF-κB signaling pathway and upregulating MyD88 expression. Therefore, AGAP2-AS1 may serve as a novel biomarker for prognosis and act as a therapeutic target for the trastuzumab treatment. 

Retracted: No

PubPeer comments:
 Figure 2i appears to include a set of images from Figure 3E in a previously published paper: Oncotarget (2017), doi: 10.18632 oncotarget.22058. I did not immediately notice any common authors. *** ![file] , 
 Left to right: - Fig 2f from  Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA ([Kang et al 2019] ). - Fig 2F from  Exosome-mediated transfer of lncRNA RP11-838N2.4 promotes erlotinib resistance in non-small cell lung cancer ([Zhang et al 2018] ). - **Fig 4C**. ![file] , 
 - *[left]* Fig 4d. - *[right]* Fig 5D from  Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-u03b21 Smads signaling pathway mediated Snail E-cadherin expression ([Ji et al 2015] ). - *[below]* Fig 5e,f from  MALAT1 regulates the transcriptional and translational levels of proto-oncogene RUNX2 in colorectal cancer metastasis ([Ji et al 2019] ). ![file] , 
 - *[left]* Fig 3F. - *[right]* Figs 3g, 5i from  MALAT1 regulates the transcriptional and translational levels of proto-oncogene RUNX2 in colorectal cancer metastasis ([Ji et al 2019] ). ![file] , 
 - *[left]* Fig 3D. - *[right]* Fig 7H from  Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA ([Kang et al 2018] ). ![file] - *[upper left]* Fig 3C from  Exosome-mediated transfer of lncRNA RP11u2011838N2.4 promotes erlotinib resistance in non-small cell lung cancer ([Zhang et al 2018] ). - *[upper right]* Fig 7B from  MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression ([Chen et al 2017] ). - *[below]* Fig 4B from  Long nonu2010coding RNA SNHG14 induces trastuzumab resistance of breast cancer via regulating PABPC1 expression through H3K27 acetylation ([Dong et al 2018] ). ![file] ,