MLL4 Regulates the Progression of Non-Small-Cell Lung Cancer by Regulating the PI3K/AKT/SOX2 Axis.

Abstract

PURPOSE:

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.

RESULTS:

We found that MLL4 expression was downregulated 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 NSCLC stem cell properties.

CONCLUSION:

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 NSCLC therapy.

• Authors: Yang Yang, Rongfang Qiu, Qiaoyou Weng, Ziwei Xu, Jingjing Song, Siyu Zhao, Miaomiao Meng, Dengke Zhang, Chunli Kong, Hailin Wang, Min Xu, Zhongwei Zhao, Jiansong Ji
• Journal: Cancer research and treatment (Cancer Res Treat) Vol. 55 Issue 3 Pg. 778-803 (Jul 2023) ISSN: 2005-9256 [Electronic] Korea (South)
• PMID: 36701842 (Publication Type: Journal Article)

Chemical References

• Proto-Oncogene Proteins c-akt
• Phosphatidylinositol 3-Kinases
• RNA, Small Interfering
• Histone-Lysine N-Methyltransferase
• SOX2 protein, human
• SOXB1 Transcription Factors
• MLL4 protein, human
• FOXP4 protein, human
• Forkhead Transcription Factors

Topics

• Humans
• Carcinoma, Non-Small-Cell Lung (pathology)
• Lung Neoplasms (pathology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Cell Proliferation (genetics)
• RNA, Small Interfering
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Carcinogenesis (genetics)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• SOXB1 Transcription Factors (genetics)
• Forkhead Transcription Factors (metabolism)