Suppression of Ca2+ signaling enhances melanoma progression. (30th August 2022)

• Record Type: Journal Article
• Authors: Gross, Scott; Hooper, Robert; Tomar, Dhanendra; Armstead, Alexander P; Shanas, No'ad; Mallu, Pranava; Joshi, Hinal; Ray, Suravi; Chong, Parkson Lee‐Gau; Astsaturov, Igor; Farma, Jeffrey M; Cai, Kathy Q; Chitrala, Kumaraswamy Naidu; Elrod, John W; Zaidi, M Raza; Soboloff, Jonathan
• Is Part Of: EMBO journal. Volume 41:Number 19(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-30
• Subjects: calcium -- melanoma -- metastasis -- Orai1 -- STIM1; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021110046
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: The role of store‐operated Ca 2+ entry (SOCE) in melanoma metastasis is highly controversial. To address this, we here examined UV‐dependent metastasis, revealing a critical role for SOCE suppression in melanoma progression. UV‐induced cholesterol biosynthesis was critical for UV‐induced SOCE suppression and subsequent metastasis, although SOCE suppression alone was both necessary and sufficient for metastasis to occur. Further, SOCE suppression was responsible for UV‐dependent differences in gene expression associated with both increased invasion and reduced glucose metabolism. Functional analyses further established that increased glucose uptake leads to a metabolic shift towards biosynthetic pathways critical for melanoma metastasis. Finally, examination of fresh surgically isolated human melanoma explants revealed cholesterol biosynthesis‐dependent reduced SOCE. Invasiveness could be reversed with either cholesterol biosynthesis inhibitors or pharmacological SOCE potentiation. Collectively, we provide evidence that, contrary to current thinking, Ca 2+ signals can block invasive behavior, and suppression of these signals promotes invasion and metastasis. Synopsis: The role of STIM/Orai‐mediated store‐operated Ca 2+ entry (SOCE) in melanoma is debated. This work reports a novel signaling axis linking UV exposure to cholesterol biosynthesis and suppression of SOCE, promoting aberrant cancer metabolism and invasive phenotypes. UV radiation suppresses SOCE and enhances invasiveness of melanoma cell lines in vivo . STIM‐Orai inhibition is sufficient to drive metastasis in syngeneic mice. Increased cholesterol biosynthesis is required for UV‐induced SOCE suppression and melanoma metastasis. UV‐induced SOCE reduction enhances glucose uptake and anabolic O‐GlcNAcylation, shifting melanoma cells to a more invasive phenotype. Cholesterol‐mediated SOCE suppression and increased O‐GlcNAcylation are conserved in melanoma patient explants. Abstract : UV‐induced cholesterol production decreases Orai activation and SOCE in melanoma cells, promoting invasive phenotypes and anabolic pathways.