In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and oxidative phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), which encode rate-limiting enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of forkhead box protein O1 (FoxO1), a key transcription factor that mediates activation of PCK1 and G6PC, with consequent alleviation of FoxO1-dependent gluconeogenesis. Further mechanistic studies show that p53 directly activates expression of the NAD + -dependent histone deacetylase sirtuin 6 (SIRT6), whose interaction with FoxO1 leads to FoxO1 deacetylation and export to the cytoplasm. In support of these observations, p53-mediated FoxO1 nuclear exclusion, down-regulation of PCK1 and G6PC expression, and regulation of glucose levels were confirmed in C57BL/J6 mice and in liver-specific Sirt6 conditional knockout mice. Our results provide insights into mechanisms of metabolism-related p53 functions that may be relevant to tumor suppression.

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Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the autophagy regulation machinery has been widely studied, the key epigenetic control of autophagy process still remains unknown. Here we report that the methyltransferase EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) epigenetically represses several negative regulators of the MTOR (mechanistic target of rapamycin [serine/threonine kinase]) pathway, such as TSC2, RHOA, DEPTOR, FKBP11, RGS16 and GPI. EZH2 was recruited to these genes promoters via MTA2 (metastasis associated 1 family, member 2), a component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA2 was identified as a new chromatin binding protein whose association with chromatin facilitated the subsequent recruitment of EZH2 to silenced targeted genes, especially TSC2. Downregulation of TSC2 (tuberous sclerosis 2) by EZH2 elicited MTOR activation, which in turn modulated subsequent MTOR pathway-related events, including inhibition of autophagy. In human colorectal carcinoma (CRC) tissues, the expression of MTA2 and EZH2 correlated negatively with expression of TSC2, which reveals a novel link among epigenetic regulation, the MTOR pathway, autophagy induction, and tumorigenesis.

Drug delivery systems with remotely controlled drug release capability are rather attractive options for cancer therapy. Herein, a reactive oxygen species (ROS)-sensitive polymeric nanocarrier TK-PPE@NPCe6/DOX was explored to realize remotely controlled drug release by light-activated size shrinkage. The TK-PPE@NPCe6/DOX encapsulating chlorin e6 (Ce6) and doxorubicin (DOX) was self-assembled from an innovative ROS-sensitive polymer TK-PPE with the assistance of an amphiphilic copolymer poly­(ethylene glycol)-b-poly­(ε-caprolactone) (PEG-b-PCL). Under the 660 nm red light irradiation, ROS generated by the encapsulated Ce6 were capable of cleaving the TK linker in situ, which resulted in the rapid degradation of the TK-PPE@NPCe6/DOX core. Consequently, the size of TK-PPE@NPCe6/DOX shrank from 154 ± 4 nm to 72 ± 3 nm, and such size shrinkage affected further triggered rapid DOX release. As evidenced by both in vitro and in vivo experiments, such ROS-sensitive polymeric nanocarriers with light-induced size shrinkage capability offer remarkable therapeutic effects in cancer treatment. This concept provides new avenues for the development of light-activated drug delivery systems for remotely controlled drug release in vivo.