NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy
Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downr...
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2024-11-01
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| author | Alessandra Ferraresi Ian Ghezzi Amreen Salwa Andrea Esposito Danny N. Dhanasekaran Ciro Isidoro |
| author_facet | Alessandra Ferraresi Ian Ghezzi Amreen Salwa Andrea Esposito Danny N. Dhanasekaran Ciro Isidoro |
| author_sort | Alessandra Ferraresi |
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| description | Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. Here, we further elucidate this mechanism by focusing on the molecular and cellular events regulating autophagy. Transcriptomic and Western blotting analyses revealed NKX3-2, a transcriptional factor, to be among the genes hyperexpressed in LPA-stimulated ovarian cancer cells. Bioinformatic analyses revealed that in ovarian cancer patients, the expression of <i>NKX3-2</i> positively correlates with genes involved in cell motility and migration, while it negatively correlates with macromolecular catabolic pathways. In various ovarian cancer cell lines, NKX3-2 silencing abrogated LPA-induced cell migration. Mechanistically, this effect is linked to the restoration of the HDAC6-mediated relocation of the lysosomes in the para-golgian area, and this results in an increase in autolysosome formation and the overall upregulation of autophagy. Silencing the expression of <i>ATG7</i> or <i>BECN1</i>, two autophagy genes, rescued the migratory phenotype of the NKX3-2-silenced ovarian cancer cells. Taken together, these data reveal the mechanism by which the LPA-NKX3-2 axis promotes the invasiveness of ovarian cancer cells and supports the possibility of targeting NKX3-2 to reduce the migratory capacity of cancer cells in response to a permissive microenvironment. |
| format | Article |
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| issn | 2073-4409 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-ec5befd901fb45bba6b168d5e0e20f0e2025-08-20T02:13:13ZengMDPI AGCells2073-44092024-11-011321181610.3390/cells13211816NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of AutophagyAlessandra Ferraresi0Ian Ghezzi1Amreen Salwa2Andrea Esposito3Danny N. Dhanasekaran4Ciro Isidoro5Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyStephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USALaboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalySeveral soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. Here, we further elucidate this mechanism by focusing on the molecular and cellular events regulating autophagy. Transcriptomic and Western blotting analyses revealed NKX3-2, a transcriptional factor, to be among the genes hyperexpressed in LPA-stimulated ovarian cancer cells. Bioinformatic analyses revealed that in ovarian cancer patients, the expression of <i>NKX3-2</i> positively correlates with genes involved in cell motility and migration, while it negatively correlates with macromolecular catabolic pathways. In various ovarian cancer cell lines, NKX3-2 silencing abrogated LPA-induced cell migration. Mechanistically, this effect is linked to the restoration of the HDAC6-mediated relocation of the lysosomes in the para-golgian area, and this results in an increase in autolysosome formation and the overall upregulation of autophagy. Silencing the expression of <i>ATG7</i> or <i>BECN1</i>, two autophagy genes, rescued the migratory phenotype of the NKX3-2-silenced ovarian cancer cells. Taken together, these data reveal the mechanism by which the LPA-NKX3-2 axis promotes the invasiveness of ovarian cancer cells and supports the possibility of targeting NKX3-2 to reduce the migratory capacity of cancer cells in response to a permissive microenvironment.https://www.mdpi.com/2073-4409/13/21/1816autophagylysosomeBAPX1HDAC6lysophosphatidic acidepithelial to mesenchymal transition |
| spellingShingle | Alessandra Ferraresi Ian Ghezzi Amreen Salwa Andrea Esposito Danny N. Dhanasekaran Ciro Isidoro NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy Cells autophagy lysosome BAPX1 HDAC6 lysophosphatidic acid epithelial to mesenchymal transition |
| title | NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy |
| title_full | NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy |
| title_fullStr | NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy |
| title_full_unstemmed | NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy |
| title_short | NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy |
| title_sort | nkx3 2 induces ovarian cancer cell migration by hdac6 mediated repositioning of lysosomes and inhibition of autophagy |
| topic | autophagy lysosome BAPX1 HDAC6 lysophosphatidic acid epithelial to mesenchymal transition |
| url | https://www.mdpi.com/2073-4409/13/21/1816 |
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