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Cytoplasmic Miz1 Suppresses TNF-α-Induced NF-κB Activation and Hepatocellular Carcinoma Progression via the Interaction with Metadherin

ABSTRACT: Previous studies have revealed that nuclear Miz1 is implicated in the regulation of several cancers mainly relying on its POZ domain. Current study, however, uncovers an unexpected function of cytoplasmic Miz1 in hepatocellular carcinoma (HCC). In vivo HCC models in Miz1 and Miz1(POZ) KO mice along with RNA-sequencing experiments show that hepatocyte specific ablation of Miz1 exacerbates TNF-α-induced NF-κB activation and promotes the progression of HCC independent of its transcriptional activity. Ubiquitination and proteosomal degradation of cytoplasmic Miz1 liberates its novel partner Metadherin (MTDH), and its site specific phosphorylation is critical to NF-κB activation. These findings reveal a brand new role of cytosolic Miz1 as a suppressor of HCC, and provide profound insights into liver cancer diagnosis and treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE104940 | GEO | 2020/10/11

REPOSITORIES: GEO

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Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and âreprogramsâ the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development. In this study, we show that Myc and N-myc differ in their affinity for Miz1, and Myc/Miz1 interaction is required for Group3 medulloblastoma (MB). The gene expression profiles of these tumors were compared to our previously published Group3 MB model as well as SHH model of MB (Kawachi et al., 2012, Cancer Cell). Cerebellar granule neuron progenitors (GNPs) [dka220-222] from postnatal (P) 6 Math1-GFP;Trp53-/-;Cdkn2c-/-. For SHH medulloblastomas, [dka204-206] and [blm015-017 or dka050-dka051], spontaneous medulloblastomas from Cdkn2c-/-;Trp53Fl/Fl;Nestin-Cre (Kawachi et al., 2012, Cancer Cell) and Ptch1+/-;Cdkn2c-/- (Uziel et al., 2005, Genes Dev) were used, respectively. Myc- [dka201-203] and MycV394D (termed MycVD thereafter)- [bvo017-bvo023] tumors were from Trp53-/-;Cdkn2c-/- cerebella of P6-P7 pups. Myc/ÎPOZ tumors [bvo002-bvo006] were obtained from Trp5Fl/Fl;Miz1ÎPOZ/POZ;Nestin-Cre cerebella of P6-P7 pups.

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Cytoplasmic Miz1 Suppresses TNF-α-Induced NF-κB Activation and Hepatocellular Carcinoma Progression via the Interaction with Metadherin

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