The activation of mTOR signalling modulates DNA methylation by enhancing DNMT1 translation in hepatocellular carcinoma.

BACKGROUND: Both dysregulation of mechanistic target of rapamycin (mTOR) signalling and DNA methylation patterns have been shown to be closely associated with tumor progression and serve as promising targets for hepatocellular carcinoma (HCC) therapy. Although their respective roles in HCC have been extensively revealed, the existence of molecular interactions between them remains largely unknown. METHODS: The association of DNA methylation and mTOR signalling in HCC tissues and cell lines was assessed. A Kaplan‒Meier analysis was applied to estimate the overall survival (OS) and recurrence-free survival (RFS) of HCC patients. The modulation of DNMT1 by mTOR in HCC cell lines was determined. The effect of the drug combination in cell lines and mouse models was examined. RESULTS: The results showed that the DNA methylation level was positively associated with the activation of mTOR signalling in HCC tissues and cell lines. Moreover, HCC patients with higher DNA methylation levels and enhanced activation of mTOR signalling exhibited the worst prognosis. Then, we screened methylation-related enzymes and found that the activation of mTOR signalling increased DNMT1 expression and activity. In addition, mTOR enhanced the translational efficiency of DNMT1 in a 4E-BP1-dependent manner, which is based on the pyrimidine rich translational element (PRTE)-containing 5'UTR of DNMT1. Moreover, we demonstrated that the combined inhibition of mTOR and DNMT synergistically inhibited HCC growth in vitro and in vivo. CONCLUSIONS: In addition to some already identified pro-cancer downstream molecules, the activation of mTOR signalling was found to promote DNA methylation by increasing the translation of DNMT1. Furthermore, combined targeting of mTOR and DNMT1 has been demonstrated to have a more effective tumor suppressive function in HCC.

Porphyran From Porphyra haitanensis Alleviates Obesity by Reducing Lipid Accumulation and Modulating gut Microbiota Homeostasis.

Porphyran possesses various activities, while the effects of the porphyran from Porphyra haitanensis (PPH) on obesity are rarely reported. In this study, C57BL/6J male mice were fed with HFD combined with PPH gavage (50 mg/kg/d) for 16 weeks, and body weight was measured once a week. After that, serum, adipose, and liver tissues were collected for physiological and biochemical analyses. Our research indicated that PPH treatment alleviated obesity in HFD-fed mice. PPH alleviated fat accumulation in serum, liver, and adipose tissues. In addition, PPH activated the AMPK-HSL/ACC pathway in epididymal adipose tissue to reduce lipid accumulation. Moreover, PPH turned white adipose into brown and activated the PGC 1α-UCP 1-mitochondrial pathway in scapular adipose tissue to generate more heat. Interestingly, PPH regulated colonic microbiota homeostasis in obese mice, including significant elevation of Roseburia and Eubacterium and marked reduction of Helicobacter. Moreover, Spearman's correlation analysis demonstrated that regulation of gut microbiota can decrease lipid accumulation. In summary, our study illustrated that PPH possesses the potential to be developed as an anti-obesity agent.