ELK1-Induced upregulation of long non-coding TNK2-AS1 promotes the progression of acute myeloid leukemia by EZH2-mediated epigenetic silencing of CELF2

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2023-01, Vol.22 (1), p.117-130
• Main Authors: Guo, Dongfang, Zhang, Airong, Suo, Meifang, Wang, Ping, Liang, Yile
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; CELF Proteins - genetics; CELF Proteins - metabolism; CELF2; Cell Line, Tumor; Cell Proliferation - genetics; ELK1; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; EZH2; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute - pathology; LncRNA TNK2-AS1; MicroRNAs - genetics; Nerve Tissue Proteins - genetics; Phosphatidylinositol 3-Kinases - metabolism; Research Paper; RNA, Long Noncoding - genetics; Up-Regulation
• ISSN: 1538-4101; 1551-4005
• DOI: 10.1080/15384101.2022.2109898

Acute myeloid leukemia (AML) is the second most common hematological malignancy after lymphoma in the world. Long non-coding RNAs (LncRNAs) have been suggested as key regulators of cancer development and progression in AML. As a member of lncRNA family, the biological role and mechanisms of tyrosine kinase non receptor 2 antisense RNA 1 (TNK2-AS1) in AML is still unclear. The expression of TNK2-AS1 was measured with RT-qPCR in AML cell lines. The changes of the proliferation, apoptosis, and differentiation in TNK2-AS1 shRNA-transfected HL-60 and THP-1 cells were detected with CCK-8, EdU, flow cytometry, Western blot, and NBT assays. Molecular control of TNK2-AS1 on CUGBP Elav-like family member 2 (CELF2) and ETS domain-containing protein-1 (ELK1) on TNK2-AS1 was assessed by chromatin immunoprecipitation (ChIP), RT-qPCR, Western blot, and RNA immunoprecipitation (RIP) assays. TNK2-AS1 expression was upregulated in AML cell lines and negatively correlated with survival patients. Knockdown of TNK2-AS1 markedly reduced AML cell proliferation and promoted apoptosis and differentiation. Likewise, TNK2-AS1 knockdown significantly suppressed tumor growth in vivo. Mechanistically, the upregulation of TNK2-AS1 was activated by transcription factor ELK1. We also uncovered that TNK2-AS1 exerted tumor-promoting effect through silencing CELF2 via binding with EZH2, thus activating PI3K/Akt pathway in AML cells. Elevated expression of TNK2-AS1 was induced by ELK1 and facilitated AML progression by suppressing CELF2 expression via EZH2-mediated epigenetic silencing, suggesting TNK2-AS1 may be a promising therapeutic target and prognostic marker for AML patients.