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LSD1-mediated stabilization of SEPT6 protein activates the TGF-β1 pathway and regulates non-small-cell lung cancer metastasis

Cancer Gene Therapy volume 29, pages 189–201 (2022)Cite this article

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Abstract

Non-small cell lung cancer (NSCLC) is a prevalent cancer with unfavorable prognosis. Over the past decade accumulating studies have reported an involvement of lysine-specific histone demethylase 1 (LSD1) in NSCLC development. Here, we aimed to explore whether LSD1 affects the metastasis of NSCLC by mediating Septin 6 (SEPT6) through the TGF-β1 pathway. RT-qPCR was used to determine LSD1 and SEPT6 expression in NSCLC tissues and cells. Interactions between LSD1, SEPT6, and TGF-β1 were detected using lentivirus-mediated silencing of LSD1 and overexpression of SEPT6. The role of LSD1 and SEPT6 in mediating the biological behavior of NSCLC cells was determined using the EdU proliferation assay, Transwell assay, and flow cytometry. Thereafter, transplanted cell tumors into nude mice were used to explore the in vivo effects of LSD1 and SEPT6 on metastasis of NSCLC. LSD1 and SEPT6 were overexpressed in NSCLC tissue and cell samples. LSD1 could demethylate the promoter of the SEPT6 to positively regulate SEPT6 expression. LSD1 promoted proliferation, migration, and invasion, while suppressing the apoptosis of NSCLC cells by increasing SEPT6 expression. LSD1-mediated SEPT6 accelerated in vivo NSCLC metastasis through the TGF-β1/Smad pathway. Collectively, LSD1 demethylates SEPT6 promoter to upregulate SEPT6, which activates TGF-β1 pathway, thereby promoting metastasis of NSCLC.

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Fig. 1: LSD1 and SEPT6 were highly expressed in NSCLC.
Fig. 2: LSD1 promotes proliferation, migration, and invasion, while suppressing apoptosis of NSCLC cells.
Fig. 3: LSD1 positively regulates SEPT6 expression through demethylation.
Fig. 4: LSD1 promotes proliferation, migration, and invasion while suppressing apoptosis of NSCLC cells by upregulating SEPT6 expression.
Fig. 5: LSD1-mediated SEPT6 to promote metastasis of NSCLC in vivo.
Fig. 6: LSD1 promotes NSCLC metastasis through the TGF-β1/Smad pathway.
Fig. 7: A graphical representation of the regulatory axis consisting of LSD1, SEPT6, and TGF-β1 during NSCLC progression.

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  1. Department of Oncology, Quanzhou First Hospital Affiliated Fujian Medical University, Quanzhou, P.R. China

    Yanni Hong, Xiaofeng Li & Jinfeng Zhu

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Correspondence to Yanni Hong.

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Hong, Y., Li, X. & Zhu, J. LSD1-mediated stabilization of SEPT6 protein activates the TGF-β1 pathway and regulates non-small-cell lung cancer metastasis. Cancer Gene Ther 29, 189–201 (2022). https://doi.org/10.1038/s41417-021-00297-6

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