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LRPPRC sustains Yap-P27-mediated cell ploidy and P62-HDAC6-mediated autophagy maturation and suppresses genome instability and hepatocellular carcinomas

Abstract

Mutants in the gene encoding mitochondrion-associated protein LRPPRC were found to be associated with French Canadian Type Leigh syndrome, a human disorder characterized with neurodegeneration and cytochrome c oxidase deficiency. LRPPRC interacts with one of microtubule-associated protein family MAP1S that promotes autophagy initiation and maturation to suppress genomic instability and tumorigenesis. Previously, although various studies have attributed LRPPRC nuclear acid-associated functions, we characterized that LRPPRC acted as an inhibitor of autophagy in human cancer cells. Here we show that liver-specific deletion of LRPPRC causes liver-specific increases of YAP and P27 and decreases of P62, leading to an increase of cell polyploidy and an impairment of autophagy maturation. The blockade of autophagy maturation and promotion of polyploidy caused by LRPPRC depletion synergistically enhances diethylnitrosamine-induced DNA damage, genome instability, and further tumorigenesis so that LRPPRC knockout mice develop more and larger hepatocellular carcinomas and survive a shorter lifespan. Therefore, LRPPRC suppresses genome instability and hepatocellular carcinomas and promotes survivals in mice by sustaining Yap-P27-mediated cell ploidy and P62-HDAC6-controlled autophagy maturation.

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Fig. 1: Loss of expression of LRPPRC protein in hepatocellular carcinomas developed in mice.
Fig. 2: LRPPRC suppresses hepatocarcinogenesis and promotes survival in DEN-treated mice.
Fig. 3: LRPPRC sustains cell ploidy.
Fig. 4: LRPPRC suppresses DNA damage.
Fig. 5: LRPPRC regulates proteins involved in Hippo signal pathway and autophagy regulation.
Fig. 6: LRPPRC interacts with Yap to regulate the subcellular distribution of P27.
Fig. 7: LRPPRC regulates the degradation of autophagosomes.

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Acknowledgements

We thank Dr Nils-Göran Larsson, Department of Mitochondrial Genetics, Max Planck Institute for Biology of Ageing, Cologne, Germany, for providing LRPPRCloxP/loxP mice to us as a gift. This work was supported by National Natural Science Foundation of China (81772931) and NCI R01CA142862 to Leyuan Liu.

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WL and LL designed the study, interpreted data, and wrote the manuscript. WL, YD, BS, and LL performed the experiments and analyzed data. FY, JZ, GX, XJ, FW, and XZ contributed to experimental design, data interpretation, or research resources. All authors reviewed the manuscript and accepted final version.

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Correspondence to Leyuan Liu.

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Li, W., Dai, Y., Shi, B. et al. LRPPRC sustains Yap-P27-mediated cell ploidy and P62-HDAC6-mediated autophagy maturation and suppresses genome instability and hepatocellular carcinomas. Oncogene 39, 3879–3892 (2020). https://doi.org/10.1038/s41388-020-1257-9

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