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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
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.
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.
Insights
Mixed-lineage leukemia protein 4 (MLL4) downregulation promotes non-small cell lung cancer (NSCLC) progression and metastasis. MLL4 is crucial for maintaining NSCLC stem cell properties and may serve as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Mixed-lineage leukemia protein 4 (MLL4/KMT2D) is a histone methyltransferase implicated in various cancers.
- MLL4 mutations are linked to poor prognosis in lung cancer.
Purpose of the Study:
- To investigate the role of MLL4 in lung carcinogenesis.
- To determine MLL4's function in non-small cell lung cancer (NSCLC) progression.
Main Methods:
- RNA sequencing (RNA-seq) was performed on MLL4-silenced A549 cells.
- Functional assays included EdU incorporation, colony formation, growth curves, and transwell invasion.
- In vivo bioluminescence and immunohistochemical staining were utilized.
Main Results:
- MLL4 expression is downregulated in NSCLC tissues and decreases with disease stage.
- MLL4 deficiency promotes NSCLC cell proliferation and metastasis.
- MLL4 is essential for maintaining NSCLC stem cell properties.
Conclusions:
- MLL4 plays a critical role in lung carcinogenesis via transcriptional regulation.
- MLL4 regulates the PI3K/AKT/SOX2 pathway through PIK3IP1.
- MLL4 is a potential prognostic biomarker and therapeutic target for NSCLC.
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