Xenobiotic receptors

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

(MYC-protein arginine methyltransferase 5 axis defines the tumorigenesis and immune response in hepatocellular carcinoma) Accumulating evidence has revealed the relevance of aberrant epigenetic modification changes in HCC progression. Genes affected by epigenetic alterations in HCC are highly overlapping with the MYC regulation network in genetic regulation. However, to date, there have been few studies exploring the MYC-dependent metabolic alterations and the associated the epigenetic events in HCC carcinogenesis. MYC-dependent alterations in the metabolome associated with HCC was explored by use of temporal hepatic-specific Myc disrupted mice (MycdHep/ERT2). Urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was found increased in HCC in a MYC-dependent manner. Prmt5, encoding the predominant type II arginine methyltransferase responsible for the symmetric dimethylation of arginine residues, was identified as a direct MYC target gene. These data suggested that MYC drives repressive transcription at least partially via regulating PRMT5 in HCC and targeting PRMT5 might be an alternative therapeutic approach for MYC-driven HCC. Several studies reported the role of PRMT5 in HCC,supporting our rationale of PRMT5 inhibition for HCC treatment. However, most of these studies used HCC cell lines or xenograft models and only focused on the regulation of cancer cells by PRMT5 without considering the immunogenic features in HCC. HCC is more heterogeneous than other types of solid cancer and hematological malignancies, and is not associated with a specific driver mutation. Compelling evidence indicate that the immune system strongly influences HCC development. Thus, combination use of immunotherapy with a molecular targeted agent has advanced rapidly in recent years. Notably, the current study demonstrated that inhibition of PRMT5 by GSK3326595 suppressed MYC-driven liver tumor growth in human MYC-transgenic mice that spontaneously develop HCC through both suppressed proliferation via upregulation of p27 and enhanced anti-tumor immunity via induction of lymphocyte infiltration and MHC II expression. These findings uncover the functional importance of MYC-PRMT5 axis during liver tumorigenesis, and provide a rationale for therapeutic option of MYC-driven HCC via PRMT5 inhibition from both tumorigenic and immunogenic aspects. (Feedback repression of PPARalpha signaling by Let-7 microRNA) Let-7 miRNA, which is one of the first miRNAs discovered, plays significant roles in embryogenesis, development, metabolism and oncogenesis. Let-7c belongs to the let-7 family with the mature sequence being highly similar among the family members and sharing the same target mRNAs. A previous study revealed that mature let-7c and its primary transcript, long non-coding RNA (lncRNA) AK033222 (also known as Mir99ahg), were potently and rapidly repressed by activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha), a nuclear receptor that predominantly modulates lipid metabolism. Let-7 miRNA potentiates the decay of mRNAs and inhibits protein translation related to cell proliferation, cell differentiation, immune response, and glucose metabolism. Whole body let-7 inhibition in transgenic mice expressing Lin28a or Lin28b results in resistance to hepatic steatosis and obesity, while glucose metabolism is also partially improved by a global let-7 inhibitor suggesting a role of let-7 in modulating glycolipid metabolism. However, how hepatic let-7 modulates lipid metabolism remains unknown. PPARalpha activation by synthetic Wy-14,643 or endogenous ligands was found to suppress the expression of the let-7 family, an effect dependent on hepatic PPARalpha. The biological effects of hepatic let-7 on hepatic lipid metabolism were further analyzed by use of both hepatocyte-specific let-7b/c2 knockout (let7b/c2dHep) mice and hepatocyte-specific let-7 sponge-mediated let-7 inhibition. Hepatic let-7 deficiency prevented hepatic steatosis and obesity induced by high-fat diet (HFD) feeding accompanied by inhibition of the PPARalpha signaling. Further analyses revealed that RXRalpha protein levels were decreased in let-7-disrupted hepatocytes. Ring finger protein 8 (Rnf8) was identified as a E3 ubiquitin ligase for RXRalpha and Rnf8 mRNA revealed as a direct target of let-7. These data demonstrate that hepatic let-7 deficiency improves hepatic steatosis during obesity via RNF8-RXRalpha axis, suggesting a let-7-RNF8-RXRalpha axis that may act as a negative feedback loop to attenuate PPARalpha-mediated lipid-modulating signaling.