De novo pyrimidine synthesis fuels glycolysis and confers chemoresistance in gastric cancer.

Metabolic reprogramming is a hallmark in multiple types of malignancies. Fast-growing cancer cells require facilitated synthesis of essential metabolites and excessive energy production. However, whether they are internally coordinated remains largely unknown. Herein, we found that de novo pyrimidine synthesis enhanced aerobic glycolysis in cancer cells. Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize γ-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. Collectively, our findings provide more insights into the regulation of aerobic glycolysis and a metabolic vulnerability that can be exploited to enhance chemotherapy efficacy in gastric cancer.

pVHL promotes lysosomal degradation of YAP in lung adenocarcinoma.

Yes-associated protein (YAP) is a vital transcriptional co-activator that activates cell proliferation and evasion of apoptosis for the promotion of tumorigenesis. The von Hippel-Lindau tumor suppressor protein (pVHL), as a critical component of E3 ubiquitin ligase, targets various substrates to regulate tumor progression. However, the precise molecular mechanisms of pVHL during tumorigenesis remain largely unclear. Herein, we found that there was a significant negative correlation between pVHL and YAP at protein level in the TCGA-LUAD dataset and our cohort. Over-expression of pVHL decreased YAP protein expression and reduced its transcriptional activity. Further study indicated that pVHL did not affect YAP mRNA level but decreased YAP protein stability in a lysosome-dependent manner. In addition, the pVHL-mediated degradation of YAP inhibited cellular proliferation, migration, and enhanced chemosensitivity to cisplatin in lung adenocarcinoma cells. Interestingly, the pVHL-mediated YAP degradation was blocked by elevated O-GlcNAcylation. Collectively, our findings demonstrate that pVHL modulates the lysosomal degradation of YAP, and may provide more clues to better understanding the tumor suppressive effects of pVHL.

Up-regulation of FUT8 inhibits TGF-ß1-induced activation of hepatic stellate cells during liver fibrogenesis.

Liver fibrosis is a continuous wound healing response caused by chronic liver injury, and the activation of hepatic stellate cells (HSCs) is considered as the main event for it. Core fucosylation catalyzed by FUT8 refers to adding the fucosyl moiety to the innermost GlcNAc residue of N-linked oligosaccharides and is involved in many biological processes such as cell differentiation, migration, and signaling transduction. Aberrant core fucosylation is associated with a variety of diseases including cardiovascular disease, tumors and neuroinflammation, but much less is understood in liver fibrosis. Herein, we reported FUT8 mRNA level was increased in patients with liver fibrosis from GEO database and positively correlated with fibrosis progression. FUT8 expression and the core fucosylation were also elevated in TAA-induced mouse liver fibrosis model, and were mainly distributed in the fibrous septum of mouse liver. TGF-ß1, as the most pro-fibrogenic cytokine, could promote the expression of FUT8 and total core fucosylation levels in HSCs in vitro. However, up-regulation of FUT8 in turn inhibited TGF-ß1-induced trans-differentiation, migration and pro-fibrogenic signaling pathways in HSCs. In conclusion, our results suggest that the up-regulation of FUT8 inhibits TGF-ß1-induced HSC activation in a negative feedback loop, and provide potential new therapeutic strategy for liver fibrosis by targeting FUT8.

RACK1 promotes the invasive activities and lymph node metastasis of cervical cancer via galectin-1.

Cervical cancer remains the first leading cause of cancer-related mortality among female reproductive system malignancies worldwide, and invasion and lymph node metastasis of cervical cancer represent the major reason for its poor prognosis. In this study, we found that RACK1 facilitated tumor cell invasion and lymphatic tube formation in vitro, as well as promoted lymphangiogenesis and lymph node metastasis in vivo in a galectin-1-dependent manner. Mechanism studies revealed that RACK1 promoted the expression and secretion of galectin-1 by reducing miR-1275 levels. Additionally, RACK1 also augmented galectin-1-induced downstream MEK/ERK, FAK, and AKT signaling via integrin-ß1 in cervical cancer cells. Tissue microarray confirmed that RACK1 was upregulated in squamous intraepithelial lesion and cancer, and RACK1 was positively correlated with invasion/metastasis phenotype, galectin-1 expression, and unfavorable prognosis in cervical cancer cases. Human papillomavirus E6 oncogene contributes to increased expression of RACK1 via the enhancement of its O-GlcNAcylation and protein stability. Together, our results demonstrate that RACK1 stimulates tumor invasion and lymph node metastasis of cervical cancer via galectin-1 and imply that targeting RACK1/galectin-1 axis provides promising means for cervical cancer treatment.