PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity

Protein arginine methyltransferase 5 (PRMT5) controls diverse cellular processes and is implicated in cancer development and progression. Here, we report an inverse correlation between PRMT5 function and antitumor immunity. PRMT5 expression was associated with an antitumor immune gene signature in human melanoma tissue. Reducing PRMT5 activity antagonized melanoma growth in immunocompetent but not immunocompromised mice. PRMT5 methylation of IFI16 [interferon-γ (IFN-γ)-inducible protein 16] or its murine homolog IFI204, which are components of the cGAS/STING (stimulator of IFN genes) pathway, attenuated cytosolic DNA-induced IFN and chemokine expression in melanoma cells. PRMT5 also inhibited transcription of the gene encoding NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5), a protein that promotes the expression of genes implicated in major histocompatibility complex class I (MHCI) antigen presentation. PRMT5 knockdown augmented IFN and chemokine production and increased MHCI abundance in melanoma. Increased expression of IFI204 and NLRC5 was associated with decreased melanoma growth in murine models, and increased expression of IFI16 and NLRC5 correlated with prolonged survival of patients with melanoma. Combination of pharmacological (GSK3326595) or genetic (shRNA) inhibition of PRMT5 with immune checkpoint therapy limited growth of murine melanoma tumors (B16F10 and YUMM1.7) and enhanced therapeutic efficacy, compared with the effect of either treatment alone. Overall, our findings provide a rationale to test PRMT5 inhibitors in immunotherapy-based clinical trials as a means to enhance an antitumor immune response

The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors.

Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9–driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors