FBXO38 mediates FGL1 ubiquitination and degradation to enhance cancer immunity and suppress inflammation.

Upregulation of FGL1 helps tumors escape from immune surveillance, and therapeutic antibodies targeting FGL1 have potential as another immune checkpoint inhibitor. However, the underlying mechanism of high FGL1 protein level in cancers is not well defined. Here, we report that FBXO38 interacts with and ubiquitylates FGL1 to negatively regulate its stability and to mediate cancer immune response. Depletion of FBXO38 markedly augments FGL1 abundance, not only suppressing CD8+ T cell infiltration and enhancing immune evasion of tumor but also increasing inflammation in mice. Importantly, we observe a negative correlation of FBXO38 with FGL1 and IL-6 in non-small cell lung cancer specimens. FGL1 and IL-6 levels positively correlate with TNM (tumor, lymph node, metastasis) stages, while FBXO38 and the infiltrating CD8+ T cells negatively correlate with TNM stages. Our study identifies a mechanism regulating FGL1 stability and a target to enhance the immunotherapy and suggests that the combination of anti-FGL1 and anti-IL-6 is a potential therapeutic strategy for cancer immunotherapy.

TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential.

Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC "eraser" by mRNA oxidation, abolishes YBX1-HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.

Intestinal microbial 16S sequencing and LC-MS metabonomic analysis revealed differences between young and old cats.

With the progress of society, the health problems of pets have attracted more and more attention. Recent studies have shown that intestinal microflora and related fecal metabolites play a crucial role in the healthy growth of cats. However, the potential role and related metabolic characteristics of gut microbiota in different age groups of pet cats need to be further clarified. 16S rRNA gene sequencing was used to analyze the intestinal microbial composition of young and old cats. LC-MS metabonomic analysis is used to characterize the changes in the metabolic spectrum in feces. The potential relationship between intestinal microorganisms and metabolites, as well as the differences in different age groups, were studied. The species composition of intestinal microflora in the young group and old group is significantly different, T-test algorithm shows 36 different ASVs and 8 different genuses, while the Wilcoxon algorithm shows 81 different ASVs and 17 different genuses. The metabolomics analysis identified 537 kinds of fecal metabolites, which are rich in differences between young and old cats, and may be potential biomarkers indicating the health of cats. 16S rRNA analysis showed significant differences in fructose and mannose metabolism, while metabonomics KEGG analysis showed significant difference in choline metabolism in cancer. Our study compared the differences between the intestinal microbiome and fecal metabolites in young and old cats. This difference provides a new direction for further exploring the relationship between the composition and metabolism of intestinal microbiota in cats of different age groups. It also provides a reference for cat health research.

TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling.

Inactivating mutations of von Hippel-Lindau (VHL) are highly prevalent in clear cell renal cell carcinoma (ccRCC). Improved understanding of the vulnerabilities of VHL-deficient ccRCC could lead to improved treatment strategies. The activity of DNA dioxygenase ten-eleven translocation (TET)2 is significantly reduced in multiple cancers by different mechanisms, but its role in ccRCC progression remains unclear. Here, we report that increased expression of TET2, but not TET1 and TET3, is negatively associated with tumor metastasis and advanced tumor stage and is positively associated with good prognosis uniquely in ccRCC among all 33 types of cancer in The Cancer Genome Atlas datasets. TET2 restrained glycolysis and pentose phosphate pathway metabolism in a VHL deficiency-dependent manner, thereby suppressing ccRCC progression. Notably, TET2 and VHL mutations tended to cooccur in ccRCC, providing genetic evidence that they cooperate to inhibit the progression of ccRCC. Mechanistically, TET2 was recruited by transcription factor HNF4α to activate FBP1 expression, which antagonized the function of hypoxia-inducible factor-1/2α (HIF1/2α) in metabolic reprogramming to impede ccRCC growth. Stimulating the TET2-FBP1 axis with vitamin C repressed the growth of VHL-deficient ccRCC with wild-type TET2 and increased the sensitivity to glycolysis inhibitors. Moreover, combined expression levels of the HNF4α-TET2-FBP1 axis served as a biomarker of prognosis in patients with ccRCC. This study reveals a unique function of TET2 in the suppression of tumor metabolism and HIF signaling, and it also provides therapeutic targets, potential drugs, and prognostic markers for the management of ccRCC. SIGNIFICANCE: The identification of TET2-mediated inhibition of HIF signaling and tumor metabolic reprogramming provides insights for new therapeutic strategies for VHL-deficient ccRCC.