NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Autophagy*/drug effects ; Autophagy*/genetics ; Cell Movement*/genetics ; Ovarian Neoplasms*/pathology ; Ovarian Neoplasms*/genetics ; Ovarian Neoplasms*/metabolism ; Homeodomain Proteins*/metabolism ; Homeodomain Proteins*/genetics ; Transcription Factors*/metabolism ; Transcription Factors*/genetics ; Lysosomes*/metabolism ; Histone Deacetylase 6*/metabolism ; Histone Deacetylase 6*/genetics; Humans ; Female ; Cell Line, Tumor ; Lysophospholipids/metabolism ; Gene Expression Regulation, Neoplastic

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 NKX3-2 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 ATG7 or BECN1 , 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.

Front Oncol. 2020 Dec 07;10:599915. (PMID: 33364196)
EMBO J. 2015 Apr 1;34(7):856-80. (PMID: 25712477)
Nat Protoc. 2006;1(1):179-85. (PMID: 17406230)
PLoS One. 2018 Oct 11;13(10):e0205537. (PMID: 30308041)
Cancer Lett. 2019 Feb 1;442:464-474. (PMID: 30503552)
J Hepatocell Carcinoma. 2024 May 16;11:879-900. (PMID: 38770169)
Biochem Biophys Res Commun. 2017 Apr 29;486(2):285-292. (PMID: 28315334)
Cell Mol Neurobiol. 2022 Jan;42(1):155-171. (PMID: 34106361)
Cells. 2021 Nov 17;10(11):. (PMID: 34831435)
J Clin Invest. 2015 Jan;125(1):42-6. (PMID: 25654549)
Oncol Lett. 2021 Oct;22(4):719. (PMID: 34429759)
Autophagy. 2011 Aug;7(8):927-8. (PMID: 21521941)
Front Oncol. 2017 Feb 22;7:24. (PMID: 28275576)
Traffic. 2008 Apr;9(4):574-87. (PMID: 18182013)
Cancer Res. 2018 Apr 15;78(8):1923-1934. (PMID: 29386184)
Stem Cells Dev. 2015 Jul 1;24(13):1521-35. (PMID: 25715123)
Front Biol (Beijing). 2014 Oct;9(5):376-381. (PMID: 27158253)
Medicina (Kaunas). 2023 Oct 06;59(10):. (PMID: 37893500)
Cells. 2021 Aug 11;10(8):. (PMID: 34440828)
J Biol Chem. 2012 Jan 20;287(4):2317-27. (PMID: 22069321)
EMBO J. 2017 Jul 3;36(13):1811-1836. (PMID: 28596378)
J Recept Signal Transduct Res. 2015;35(6):578-84. (PMID: 26393967)
Front Cell Dev Biol. 2021 Feb 26;9:642494. (PMID: 33718382)
Mol Cell Biol. 2003 Dec;23(23):8704-17. (PMID: 14612411)
Mol Carcinog. 2017 Mar;56(3):1164-1181. (PMID: 27787915)
Cells. 2024 Mar 05;13(5):. (PMID: 38474423)
FASEB J. 2020 Oct;34(10):13935-13948. (PMID: 32851734)
Nat Commun. 2015 Dec 10;6:8752. (PMID: 26658462)
PLoS One. 2018 May 10;13(5):e0197194. (PMID: 29746601)
Cell. 2003 Dec 12;115(6):727-38. (PMID: 14675537)
PLoS One. 2012;7(7):e39642. (PMID: 22768305)
CA Cancer J Clin. 2024 Jan-Feb;74(1):12-49. (PMID: 38230766)
Eur J Pharm Sci. 2019 Jun 15;134:116-137. (PMID: 30981885)
Mol Oncol. 2015 Oct;9(8):1612-25. (PMID: 26022108)
J Inflamm (Lond). 2022 Jul 16;19(1):11. (PMID: 35842650)
Dev Cell. 2001 Sep;1(3):411-22. (PMID: 11702952)
Sci Rep. 2020 Jul 2;10(1):10877. (PMID: 32616784)
Autophagy. 2021 Jan;17(1):1-382. (PMID: 33634751)
Cancers (Basel). 2021 Nov 10;13(22):. (PMID: 34830777)
Front Cell Dev Biol. 2020 Nov 26;8:605609. (PMID: 33330506)
Cells. 2024 May 09;13(10):. (PMID: 38786034)
EMBO J. 2010 Mar 3;29(5):969-80. (PMID: 20075865)
Genes Dev. 2002 Aug 1;16(15):1990-2005. (PMID: 12154128)
Int J Mol Sci. 2018 Nov 05;19(11):. (PMID: 30400561)
Genes Cancer. 2011 May;2(5):563-75. (PMID: 21901169)
Pathobiology. 2018;85(1-2):41-49. (PMID: 29020678)

Keywords: BAPX1; HDAC6; autophagy; epithelial to mesenchymal transition; lysophosphatidic acid; lysosome; ovarian cancer

0 (Homeodomain Proteins)
0 (Transcription Factors)
PG6M3969SG (lysophosphatidic acid)
EC 3.5.1.98 (Histone Deacetylase 6)
0 (Lysophospholipids)
EC 3.5.1.98 (HDAC6 protein, human)

Date Created: 20241108 Date Completed: 20241108 Latest Revision: 20250127

20250128

PMC11544992

10.3390/cells13211816

39513923