Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.

In this research, a new type of mitochondrial-imaging probe using spindle nanocomposite with adjustable aspect ratios and enhanced upconversion luminescent (UCL) property was designed for synergistic immune–photodynamic anticancer theranostics. Gold nanoparticles are coated on the surface of a spindle-like probe layer-by-layer (LBL), which makes the probe have better red UCL enhancement under the NIR excitation, and the surface plasmon resonance (SPR) peak can be exactly predicted by discrete dipole scattering calculation. The mitochondrial imaging experiments show that the probe modified with ethylenebis­(nitrilodimethylene)­tetraphosphonic acid (EDTMP) has better biocompatibility and can achieve real-time dynamic imaging of mitochondria, revealing its potential preclinical bioimaging use. In addition, a monoclonal antibody of anti-CTLA-4 was used as an immune checkpoint blockade to promote the activation of immune response and enhance the photodynamic therapy (PDT) to kill cancer cells. The in vivo compatibility, blood routine, bioimaging, and anticancer results reveal that the combination of SPS@Au and ZnPc (SPSZ) was a potential synergistic immune–photodynamic therapy (PDT) candidate with enhanced UCL and good biocompatibility.

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