DCN1

Nuclear factor kappa-B (NF-κB) signaling-mediated inflammation contributes greatly to the pathogenesis of periodontitis. Neddylation, a ubiquitin-like posttranslational modification, is known to regulate NF-κB signaling. DCUN1D1 (defective in cullin neddylation 1 domain containing 1) is a critical factor in neddylation and has been shown to regulate NF-κB activation. However, the previse roles of DCUN1D1 in periodontitis are not fully elucidated. To explore the roles of DCUN1D1 in periodontitis, the expression of DCUN1D1 was measured in gingival tissues of patients with periodontitis. We inhibited DCUN1D1 by siRNA knocking down or using inhibitor in gingival fibroblasts and the lipopolysaccharides (LPS)-induced expression of IL-6 and TNF-α, and activation of NF-κB were measured. The expression of DCUN1D1 was increased in gingival tissues of patients with periodontitis. Knocking down or inhibiting DCUN1D1 suppressed LPS-induced production of IL-6 and TNF-α, decreased NF-κB activity, and inhibited LPS-induced activation of NF-κB. Inhibiting DCUN1D1 ameliorates periodontitis by suppressing NF-κB signaling.

Abnormally high expression of lysine-specific demethylase 1 A (LSD1) and DCN1 plays a vital role in the occurrence, development, and poor prognosis of non-small cell lung cancer (NSCLC). Accumulating evidence has shown that the development of small-molecule inhibitors dually targeting LSD1 and the DCN1-UBC12 interaction probably have therapeutic promise for cancer therapy. This work reported that WS-384 dually targeted LSD1 and DCN1-UBC12 interactions and evaluated its antitumor effects in vitro and in vivo. Specifically, WS-384 inhibited A549 and H1975 cells viability and decreased colony formation and EdU incorporation. WS-384 could also trigger cell cycle arrest, DNA damage, and apoptosis. Moreover, WS-384 significantly decreased tumor weight and volume in A549 xenograft mice. Mechanistically, WS-384 increased the gene and protein level of p21 by suppressing the neddylation of cullin 1 and decreasing H3K4 demethylation at the CDKN1A promoter. The synergetic upregulation of p21 contributed to cell cycle arrest and the proapoptotic effect of WS-384 in NSCLC cells. Taken together, our proof of concept studies demonstrated the therapeutic potential of dual inhibition of LSD1 and the DCN1-UBC12 interaction for the treatment of NSCLC. WS-384 could be used as a lead compound to develop new dual LSD1/DCN1 inhibitors for the treatment of human diseases in which LSD1 and DCN1 are dysregulated.

Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes using TES-related genes and determine subtype specific drivers and treatments for hepatocellular carcinoma (HCC).

We collected 68 genesets depicting tumor biology, immune infiltration, and liver function, totaling 2831 genes, and collected mRNA profiles and clinical data for over 6000 tumors from 65 datasets in the GEO, TCGA, ICGC, and several other databases. We designed a three-step clustering pipeline to identify subtypes. The microenvironment, genomic alteration, and drug response differences were systematically compared among subtypes.

Seven subtypes (TES-1/2/3/4/5/6/7) were revealed in 159 tumors from the CHCC-HBV cohort. We constructed a single sample classifier using paired genes (sscpgsTES). TES subtypes were significantly associated with multiple clinical variables including etiology, and survival in 14 of 17 cohorts and the meta-cohort. TES-1 had the poorest prognosis and highest proliferation level. Both TES-2 and TES-7 were immune-enriched, however, TES-2 had a significantly worse prognosis, and hypoxic and immunosuppressive microenvironment. TES-4 had activated Wnt pathway, driven by CTNNB1 mutation. Good prognosis TES-6 exhibited the best differentiation. TES-5 and TES-3 were considered as novel subclasses by comparing with ten previous subtyping systems. TES-5 tumors had high AFP but good overall survival, and ∼45% of them harbored AXIN1 mutation. TES-3 was immune and stromal desert, may be driven by high copy number alteration burden, and had the poorest response to immune checkpoint inhibitor. TES-1 and TES-2 had significantly lower response to transarterial chemoembolization, but they showed significantly higher sensitivity to compound YM-155.

Tumor ecosystem subtypes expand existing HCC subtyping systems, have distinct drivers, prognosis, and treatment vulnerabilities.