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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2022.1042    [Accepted]
MLL4 Regulates the Progression of Non-Small-Cell Lung Cancer by Regulating the PI3K/AKT/SOX2 Axis
Yang Yang1,2,3 , Rongfang Qiu1,2,3, Qiaoyou Weng1,2,3, Ziwei Xu1,2,3, Jingjing Song1,2,3, Siyu Zhao1,2,3, Miaomiao Meng1,2,3, Dengke Zhang1,2,3, Chunli Kong1,2,3, Hailin Wang1,2,3, Min Xu1,2,3, Zhongwei Zhao1,2,3, Jiansong Ji1,2,3
1Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
2Department of Radiology, Clinical College of The Affiliated Central Hospital, Lishui University, Lishui, China
3Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, China
Correspondence  Zhongwei Zhao ,Tel: 86-578-2285011, Email: zhaozw79@163.com
Jiansong Ji ,Tel: 86-578-2285011, Email: jijiansong@zju.edu.cn
Received: September 6, 2022;  Accepted: January 25, 2023.  Published online: January 26, 2023.
*Yang Yang and Rongfang Qiu contributed equally to this work.
Mixed-lineage leukemia protein 4 (MLL4/KMT2D) is a histone methyltransferase, and its mutation has been reported to be associated with a poor prognosis in many cancers, including lung cancer. We investigated the function of MLL4 in lung carcinogenesis.
Materials and Methods
RNA sequencing (RNA-seq) in A549 cells transfected with control siRNA or MLL4 siRNA was performed. Also, we used EdU incorporation assay, colony formation assays, growth curve analysis, transwell invasion assays, immunohistochemical staining and in vivo bioluminescence assay to investigate the function of MLL4 in lung carcinogenesis.
We found that MLL4 expression was down-regulated in non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues and tended to decrease with disease stage progression. We analyzed the transcriptomes in control and MLL4-deficient cells using high-throughput RNA deep sequencing (RNA-seq) and identified a cohort of target genes, such as SOX2, ATF1, FOXP4, PIK3IP1, SIRT4, TENT5B, and LFNG, some of which are related to proliferation and metastasis. Our results showed that low expression of MLL4 promotes NSCLC cell proliferation and metastasis and is required for the maintenance of non-small cell lung cancer stem cell properties.
Our findings identify an important role of MLL4 in lung carcinogenesis through transcriptional regulation of PIK3IP1, affecting the PI3K/AKT/SOX2 axis, and suggest that MLL4 could be a potential prognostic indicator and target for non-small cell lung cancer therapy.
Key words: Mixed-lineage leukemia protein 4, Non-small cell lung cancer, Proliferation, Neoplasm metastasis, PI3K/AKT/SOX2 axis
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