UBXN1 promotes liver tumorigenesis by regulating mitochondrial homeostasis.

BACKGROUND: The maintenance of mitochondrial homeostasis is critical for tumor initiation and malignant progression because it increases tumor cell survival and growth. The molecular events controlling mitochondrial integrity that facilitate the development of hepatocellular carcinoma (HCC) remain unclear. Here, we report that UBX domain-containing protein 1 (UBXN1) hyperactivation is essential for mitochondrial homeostasis and liver tumorigenesis. METHODS: Oncogene-induced mouse liver tumor models were generated with the Sleeping Beauty (SB) transposon delivery system. Assessment of HCC cell growth in vivo and in vitro, including tumour formation, colony formation, TUNEL and FACS assays, was conducted to determine the effects of UBXN1 on HCC cells, as well as the involvement of the UBXN1-prohibitin (PHB) interaction in mitochondrial function. Coimmunoprecipitation (Co-IP) was used to assess the interaction between UBXN1 and PHB. Liver hepatocellular carcinoma (LIHC) datasets and HCC patient samples were used to assess the expression of UBXN1. RESULTS: UBXN1 expression is commonly upregulated in human HCCs and mouse liver tumors and is associated with poor overall survival in HCC patients. UBXN1 facilitates the growth of human HCC cells and promotes mouse liver tumorigenesis driven by the NRas/c-Myc or c-Myc/shp53 combination. UBXN1 interacts with the inner mitochondrial membrane protein PHB and sustains PHB expression. UBXN1 inhibition triggers mitochondrial damage and liver tumor cell apoptosis. CONCLUSIONS: UBXN1 interacts with PHB and promotes mitochondrial homeostasis during liver tumorigenesis.

UBXN9 inhibits the RNA exosome function to promote T cell control of liver tumorigenesis.

BACKGROUND AND AIMS: Liver tumorigenesis encompasses oncogenic activation and self-adaptation of various biological processes in premalignant hepatocytes to circumvent the pressure of cellular stress and host immune control. Ubiquitin regulatory X domain-containing proteins (UBXNs) participate in the regulation of certain signaling pathways. However, whether UBXN proteins function in the development of liver cancer remains unclear. APPROACH AND RESULTS: Here, we demonstrated that UBXN9 (Alveolar Soft Part Sarcoma Chromosomal Region Candidate Gene 1 Protein/Alveolar Soft Part Sarcoma Locus) expression was decreased in autochthonous oncogene-induced mouse liver tumors and ~47.7% of human HCCs, and associated with poor prognosis in patients with HCC. UBXN9 attenuated liver tumorigenesis induced by different oncogenic factors and tumor growth of transplanted liver tumor cells in immuno-competent mice. Mechanistically, UBXN9 significantly inhibited the function of the RNA exosome, resulting in increased expression of RLR-stimulatory RNAs and activation of the retinoic acid-inducible gene-I-IFN-Ι signaling in tumor cells, and hence potentiated T cell recruitment and immune control of tumor growth. Abrogation of the CD8 + T cell response or inhibition of tumor cell retinoic acid-inducible gene-I signaling efficiently counteracted the UBXN9-mediated suppression of liver tumor growth. CONCLUSIONS: Our results reveal a modality in which UBXN9 promotes the stimulatory RNA-induced retinoic acid-inducible gene-I-interferon signaling that induces anti-tumor T cell response in liver tumorigenesis. Targeted manipulation of the UBXN9-RNA exosome circuit may have the potential to reinstate the immune control of liver tumor growth.