Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.

Emerging evidence indicates that certain microRNAs (miRNAs) play important roles in epileptogenesis. MiR-219 is a brain-specific miRNA and has been shown to negatively regulate the function of N-methyl-D-aspartate (NMDA) receptors by targeting Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)γ. Herein, we found that the level of miR-219 was decreased in both the kainic acid (KA)-induced epilepsy model and in cerebrospinal fluid specimens of epilepsy patients. Importantly, silencing of miR-219 by its antagomir in vivo resulted in seizure behaviors, abnormal cortical electroencephalogram (EEG) recordings in the form of high-amplitude and high-frequency discharges, and increased levels of CaMKIIγ and an NMDA receptor component, NR1, in a pattern similar to that found in KA-treated mice. Moreover, treatments with the miR-219 agomir in vivo alleviated seizures, abnormal EEG recordings, and decreased levels of CaMKIIγ and NR1 in KA-treated mice. Furthermore, treatment with MK-801, an antagonist of NMDA receptors, significantly alleviated abnormal EEG recordings induced by miR-219 antagomir. Together, these results demonstrate that miR-219 plays a crucial role in suppressing seizure formation in experimental models of epilepsy through modulating the CaMKII/NMDA receptor pathway and that miR-219 supplement may be a potential anabolic strategy for ameliorating epilepsy.

Two hallmarks for cancer cells are the accelerated cell cycle progression as well as the altered metabolism, however, how these changes are coordinated to optimize the growth advantage for cancer cells are still poorly understood. Here we identify that Polo-like kinase 1 (Plk1), a key regulator for cell mitosis, plays a critical role for biosynthesis in cancer cells through activating pentose phosphate pathway (PPP). We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules. Importantly, we further demonstrate that Plk1-mediated activation of G6PD is critical for its role to promote cell cycle progression and cancer cell growth. Collectively, these findings establish a critical role for Plk1 in regulating biosynthesis in cancer cells, exemplifying how cell cycle progression and metabolic reprogramming are coordinated for cancer progression.

No abstract

Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity. Intriguingly, we find that Menin interacts directly with the TAD domain of MYC and co-localizes with MYC to E-Box to enhance the transcription of MYC target genes in a P-TEFb-dependent manner. We further demonstrate that, by transcriptionally promoting the expression of MYC target genes in cancer cells, Menin stimulates cell proliferation and cellular metabolism both in vitro and in vivo. Our results uncover a previously unappreciated mechanism by which Menin functions as an oncogenic regulatory factor that is critical for MYC-mediated gene transcription.