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      MBOAT7-Driven Phosphatidylinositol Remodeling Promotes the Progression of Clear Cell Renal Carcinoma

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          Abstract

          The most common kidney cancer, clear cell Renal Cell Carcinoma (ccRCC) is closely associated with obesity. In fact, the “clear cell” variant of RCC is given this name due to large lipid droplets within the tumor cells. Although it is well appreciated that renal lipid metabolism is altered in ccRCC, the mechanisms driving this are not well understood. Leveraging a shotgun lipidomics approach we have identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of the acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7 −/− cells fail to form tumors in vivo. RNAseq of MBOAT7 −/− cells identified alterations in cell migration and extracellular matrix organization, which were functionally validated in migration assays. Our work highlights the accumulation of AA-PI in ccRCC and demonstrate a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism, and identify MBOAT7 as a novel target in advanced ccRCC.

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          Author and article information

          Journal
          bioRxiv
          May 23 2019
          Article
          10.1101/648378
          948da4c6-784c-4817-a4e9-99e64971bab9
          © 2019
          History

          Cell biology,Molecular biology
          Cell biology, Molecular biology

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