1. A NR2E1-Interacting Peptide of LSD1 Inhibits the Proliferation of Brain Tumor Initiating Cells
- Author
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Umar F. Shahul Hameed, Pankaj Kumar Giri, Xiang Sun, Ping Yuan, Balakrishnan Shenbaga Moorthy, Fangjin Chen, Philip D. Jeffrey, Wen Zhang, Yonggao Mou, Jianfeng Pei, Xin Ma, Rong Hu, Kunchithapadam Swaminathan, and Li Zhou
- Subjects
Gene knockdown ,animal structures ,Cell ,Brain tumor ,Biology ,medicine.disease ,In vitro ,medicine.anatomical_structure ,medicine ,Cancer research ,biology.protein ,H3K4me3 ,PTEN ,Epigenetics ,Chromatin immunoprecipitation - Abstract
Background: Brain tumor initiating cells (BTICs) play a key role in the progression and relapse of the dreadful glioblastoma. Targeting the TLX involved self-renewal mechanism of BITCs may enable us to develop novel therapeutic strategy for glioblastoma. Methods: The function of NR2E (TLX) and its interacting protein-LSD1 in BTICs were characterized by gene knockdown combined with tumor sphere formation assay, cell-growth assay, co-immunoprecipitation and chromatin immunoprecipitation assays. NR2E interacting peptide of LSD1 was identified and confirmed by Amide Hydrogen/Deuterium Exchange and Mass Spectrometry (HDX-MS) and in vitro functional assay with LSD1 fragment deletion mutants. The in vivo function of the peptide was further examined with patient-derived glioblastoma initiating cell xenograft mouse model. Findings: NR2E1 recruits LSD1 to remove the active epigenetic marker H3K4me3 at Pten promoter and repress its expression, thereby promoting BTIC proliferation. LSD1 peptide (L197-211) that locates at the LSD1 SWIRM domain is critical for the interaction between NR2E1 and LSD1. Overexpression of this peptide inhibits BTIC proliferation and brain tumor growth. Interpretation: Our studies show that NR2E1 partners with LSD1 to promote the self-renewal of BTICs. Interference of NR2E1 and LSD1 interaction by peptide L197-211 may be explored as a novel therapeutic strategy for malignant brain tumors. Funding Information: This work was supported by funds from National Natural Science Foundation of China (NSFC) (Grant No. 81773156 to PY and Grant No. 8187232 to YM) and the support of the Ministry of Education of Singapore Academic Research Fund to the Singapore researchers to KS. Declaration of Interests: The authors declare that no competing interest exists. Ethics Approval Statement: The animal experiments were performed under the approval from Animal Experimentation Ethics Committee (AEEC) in the Sixth Affiliated Hospital of Sun Yatsen University.
- Published
- 2021