SLC13A2-transported citrate is a metabolic signal for PKM2 acetylation and degradation to suppress tumor growth

Background and aimsMetabolic reprogramming represents as a pivotal hallmark for cancer, but TCA cycle in tumorigenesis and progression has long been neglected. Solute carrier (SLC) transporters mediate the transport of TCA cycle intermediates across membrane, but their functions in cancer pathogenesis remains unclear. Approaches & ResultsUsing integrated analysis of solute carrier (SLC) transporters for TCA cycle intermediates, we found that SLC13A2 was consistently downregulated in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and heterogeneous mouse models. Adeno-associated virus (AAV)-transduced liver-specific knockout or overexpression of SLC13A2 promoted or ameliorated HCC progression in the primary mouse model, demonstrating that SLC13A2 served as a protective factor during HCC pathogenesis. SLC13A2 inhibited HCC cell proliferation by decreasing mitochondrial function via suppressed oxygen consumption and ATP production. Combined with metabolic flux analysis, we found that SLC13A2 imported citrate, which secreted acetyl-CoA as a precursor for the acetylation of pyruvate kinase muscle isozyme M2 (PKM2), which led to its protein degradation. Decreased activity of pyruvate kinase depleted pyruvate for the TCA cycle, thus inhibiting amino acid synthesis and nucleotide metabolism. Additionally, a decrease in nuclear PKM2 protein transduced to reprogrammed gene transcription for cell proliferation and metabolism which is required for tumor growth. ConclusionsThis study revealed that citrate transported by SLC13A2 acts as a signal to disrupt metabolic homeostasis for tumor growth and suggests potential drug targets for HCC therapy. graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/591017v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@80c95eorg.highwire.dtl.DTLVardef@124750corg.highwire.dtl.DTLVardef@809ab4org.highwire.dtl.DTLVardef@12cbe74_HPS_FORMAT_FIGEXP M_FIG C_FIG