Knockdown of MAML1 inhibits proliferation and induces apoptosis of T‐cell acute lymphoblastic leukemia cells through SP1‐dependent inactivation of TRIM59

• DOI: 10.1002/jcp.27323
• Publication Date: 2018-10-29T04:52:44Z
• Authors: Hui Cheng; Li Chen; Xiaoxia Hu; Huiying Qiu; Xiaoqian Xu; Lei Gao; Gusheng Tang; Weiping Zhang; Jianmin Wang; Jianmin Yang; Chongmei Huang
• Keywords: 0301 basic medicine; Sp1 Transcription Factor; Intracellular Signaling Peptides and Proteins; Apoptosis; Cell Cycle Checkpoints; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Tripartite Motif Proteins; 03 medical and health sciences; Cell Line, Tumor; Gene Knockdown Techniques; Humans; Receptor, Notch1; Promoter Regions, Genetic; Cell Proliferation; Signal Transduction; Transcription Factors

AbstractNotch exerts important functions in cell proliferation, survival, and differentiation, which plays a critical role in tumor development when aberrantly activated. Mastermind‐like protein 1 (MAML1) has been functioning as crucial coactivators of Notch receptors and is required for stable formation of Notch transcriptional complexes. However, the mechanism whereby MAML1 induces T‐cell acute lymphoblastic leukemia (T‐ALL) tumorigenesis is largely unknown. The CCK‐8 and flow cytometry assay were performed to examine the effect of MAML1 knockdown on T‐ALL cell proliferation, apoptosis, and cell cycle. The expression of MAML1, cell cycle, and apoptosis‐related gene, as well as TRIM family members and specific protein 1 (SP1) was measured by western blot analysis and qPCR. Our results showed that MAML1 knockdown significantly inhibited cell proliferation and induced G0/G1 cell cycle arrest and apoptosis in Jurkat and MOLT‐4 cells. Cell cycle and apoptosis‐related gene expression, including CDK2, Bcl‐2, Bax, and Bad, was modified by the MAML1 knockdown. MAML1 knockdown obviously inhibited the CDK2 and Bcl‐2 expression and increased the Bax, p53, and Bad expression. Moreover, the TRIM family members, including TRIM13, TRIM32, TRIM44, and TRIM59, were significantly decreased by the MAML1 knockdown, with the highest decrease detected in TRIM59 expression. Interesting, overexpression of SP1 not only increased the expression of MAML1 and TRIM59, but also promoted the promoter activation of TRIM59. Taken together, knockdown of MAML1 inhibits proliferation and induces apoptosis of T‐ALL cells through SP1‐dependent inactivation of TRIM59, and therefore suggest that MAML1‐SP1‐TRIM59 axis may serve as potentially interesting therapeutic targets for treatment of T‐ALL.