PIDDosome‐induced p53‐dependent ploidy restriction facilitates hepatocarcinogenesis. (23rd November 2020)

• Record Type: Journal Article
• Authors: Sladky, Valentina C; Knapp, Katja; Szabo, Tamas G; Braun, Vincent Z; Bongiovanni, Laura; van den Bos, Hilda; Spierings, Diana CJ; Westendorp, Bart; Curinha, Ana; Stojakovic, Tatjana; Scharnagl, Hubert; Timelthaler, Gerald; Tsuchia, Kaoru; Pinter, Matthias; Semmler, Georg; Foijer, Floris; de Bruin, Alain; Reiberger, Thomas; Rohr‐Udilova, Nataliya; Villunger, Andreas
• Is Part Of: EMBO reports. Volume 21:Number 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-23
• Subjects: caspase‐2 -- hepatocellular carcinoma -- p53 -- PIDD1 -- polyploidy; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202050893
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi‐protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome‐induced p53‐activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro‐tumorigenic effect of PIDDosome‐mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence‐free survival in HCC patients. Synopsis: Hepatocyte ploidy is controlled by the PIDDosome and its loss causes increased hepatocyte ploidy, which protects mice from developing liver cancer. High tumor cell density, a surrogate of low ploidy, predicts poor recurrence free survival in HCC patients. The PIDDosome promotes DEN‐induced liver cancer in mice. Liver cancer arises preferentially from hepatocytes with low ploidy. Low tumor ploidy predicts poor recurrence‐free survival in HCC patients. Abstract : Hepatocyte ploidy is controlled by the PIDDosome and its loss causes increased hepatocyte ploidy, which protects mice from developing liver cancer. High tumor cell density, a surrogate of low ploidy, predicts poor recurrence free survival in HCC patients.