Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression

• Published in: International journal of molecular sciences Vol. 21; no. 13; p. 4786
• Main Authors: Bery, Fanny, Figiel, Sandy, Kouba, Sana, Fontaine, Delphine, Guéguinou, Maxime, Potier-Cartereau, Marie, Vandier, Christophe, Guibon, Roseline, Bruyère, Franck, Fromont, Gaëlle, Mahéo, Karine
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.07.2020; MDPI
• Subjects: calcium; Calcium homeostasis; Calcium influx; Calcium ions; Cell adhesion & migration; Cell Line, Tumor; Cell Movement; Communication; Control theory; Eicosapentaenoic acid; Eicosapentaenoic Acid - pharmacology; Epithelial-Mesenchymal Transition; Feedback loops; Gene expression; Glycolipids - pharmacology; Homeostasis; Humans; Hypoxia; Hypoxia - physiopathology; Linoleic acid; Linoleic Acid - pharmacology; Lipid composition; Lipids; Male; Medical prognosis; Mesenchyme; Metastasis; Positive feedback; Potassium channels; Potassium channels (calcium-gated); Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Signal transduction; Small-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Small-Conductance Calcium-Activated Potassium Channels - metabolism; Transcription factors; Tumor Microenvironment; Tumors; Zeb1; Zinc Finger E-box-Binding Homeobox 1 - metabolism; Zeb1; hypoxia; lipids; prostate cancer; calcium
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21134786

Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca -activated K+ channel, which leads to amplifying store-operated Ca entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.