Tumour cells secrete exosomes that are involved in the remodelling of the tumour–stromal environment and promoting malignancy. The mechanisms governing tumour exosome release, however, remain incompletely understood. Here we show that tumour cell exosomes secretion is controlled by pyruvate kinase type M2 (PKM2), which is upregulated and phosphorylated in tumours. During exosome secretion, phosphorylated PKM2 serves as a protein kinase to phosphorylate synaptosome-associated protein 23 (SNAP-23), which in turn enables the formation of the SNARE complex to allow exosomes release. Direct phosphorylation assay and mass spectrometry confirm that PKM2 phosphorylates SNAP-23 at Ser95. Ectopic expression of non-phosphorylated SNAP-23 mutant (Ser95→Ala95) significantly reduces PKM2-mediated exosomes release whereas expression of selective phosphomimetic SNAP-23 mutants (Ser95→Glu95 but not Ser20→Glu20) rescues the impaired exosomes release induced by PKM2 knockdown. Our findings reveal a non-metabolic function of PKM2, an enzyme associated with tumour cell reliance on aerobic glycolysis, in promoting tumour cell exosome release.

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BackgroundAttention deficit/hyperactivity disorder (ADHD), the most common childhood neurobehavioural disorder, can produce a series of negative effects on children, adolescents, and even adults as well as place a serious economic burden on families and society. However, the prevalence of ADHD is not well understood in China. The goal of this study was to estimate the pooled prevalence of ADHD among children and adolescents in China using a systematic review and meta-analysis.MethodsA systematic literature search was conducted in PubMed, Web of Science, MEDLINE, CNKI, Wanfang, Weipu and CBM databases, and relevant articles published from inception to March 1, 2016, that provided the prevalence of ADHD among children and adolescents in China were reviewed. The risk of bias in individual studies was assessed using the Risk of Bias Tool for prevalence studies. Pooled-prevalence estimates were calculated with a random-effects model. Sources of heterogeneity were explored using subgroup analyses.ResultsSixty-seven studies with a total of 275,502 individuals were included in this study. The overall pooled-prevalence of ADHD among children and adolescents in China was 6.26% (95% CI: 5.36–7.22%) with significant heterogeneity (I2 = 99.0%, P < 0.001). The subgroup analyses showed that, the variables “geographic location” and “source of information” partially explained of the heterogeneity in this study (P < 0.05). The prevalence of ADHD-I was the highest of the subtypes, followed by ADHD-HI and ADHD-C.ConclusionsThe prevalence of ADHD among children and adolescents in China is generally consistent with the worldwide prevalence and shows that ADHD affects quite a large number of people under 18 years old. However, a nationwide study is needed to provide more accurate estimations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-1187-9) contains supplementary material, which is available to authorized users.

It is well known that high-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and E7 was identified as one of the key initiators in HPV-mediated carcinogenesis. Here we show that lactate dehydrogenase A (LDHA) preferably locates in the nucleus in HPV16-positive cervical tumors due to E7-induced intracellular reactive oxygen species (ROS) accumulation. Surprisingly, nuclear LDHA gains a non-canonical enzyme activity to produce α-hydroxybutyrate and triggers DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation, resulting in the activation of antioxidant responses and Wnt signaling pathway. Furthermore, HPV16 E7 knocking-out reduces LDHA nuclear translocation and H3K79 tri-methylation in K14-HPV16 transgenic mouse model. HPV16 E7 level is significantly positively correlated with nuclear LDHA and H3K79 tri-methylation in cervical cancer. Collectively, our findings uncover a non-canonical enzyme activity of nuclear LDHA to epigenetically control cellular redox balance and cell proliferation facilitating HPV-induced cervical cancer development.

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