Dandan Yin

RNA-binding proteins (RBPs) play crucial roles in tumorigenesis and cancer treatment. As metabolic reprogramming is known to participate in tumorigenesis, elucidation of the mechanisms of crosstalk between RBPs and metabolism could provide new insights into cancer biology. Here, we found that the RBP ZC3H18 is overexpressed in lung cancer through copy number gain, which exerts oncogenic functions. Mechanistically, ZC3H18 undergoes phase separation to transcriptionally activate a key metabolic enzyme, lactate dehydrogenase A (LDHA), by binding to the LDHA promoter, thus promoting glycolysis and the production of lactate. The accumulation of lactate, in turn, activates the transcription of ZC3H18 through histone H3K18 lactylation (H3K18la) and directly induces the lactylation of ZC3H18 at the Lys186 residue (K186) in post-translational, thus forming a positive ZC3H18/LDHA/lactate/ZC3H18 feedback loop. Moreover, the combination of ZC3H18 inhibition and an LDHA small-molecule inhibitor (GSK2837808A) exhibited better antitumor efficacy in lung cancer patient-derived xenograft (PDX) model, suggesting the therapeutic potential of targeting the ZC3H18/LDHA axis. Taken together, our findings clarify the dialogue between RBP phase separation and lactate metabolism from a novel perspective and suggest that the ZC3H18/LDHA axis may serve as a potential therapeutic target for lung cancer.

The quick rearrangement of IGF2BP1 droplets. A time-lapse movie of droplets formed by IGF2BP1 undergoes a fusion event.

Supplementary Materials and Methods

C-Myc and E2F1 play critical roles in many human cancers. As long noncoding RNAs (lncRNA) are known to regulate various tumorigenic processes, elucidation of mechanisms of cross-talk between lncRNAs and c-Myc/E2F1-related signaling pathways could provide important insights into cancer biology. In this study, we used integrated bioinformatic analyses and found that the lncRNA MNX1-AS1 is upregulated in non–small cell lung cancer (NSCLC) via copy-number gain and c-Myc–mediated transcriptional activation. High levels of MNX1-AS1 were associated with poor clinical outcomes in patients with lung cancer. MNX1-AS1 promoted cell proliferation and colony formation in vitro and tumor growth in vivo. MNX1-AS1 bound and drove phase separation of IGF2BP1, which increased the interaction of IGF2BP1 with the 3′-UTR (untranslated region) of c-Myc and E2F1 mRNA to promote their stability. The c-Myc/MNX1-AS1/IGF2BP1 positive feedback loop accelerated cell-cycle progression and promoted continuous proliferation of lung cancer cells. In a lung cancer patient-derived xenograft model, inhibition of MNX1-AS1 suppressed cancer cell proliferation and tumor growth. These findings offer new insights into the regulation and function of c-Myc and E2F1 signaling in NSCLC tumorigenesis and suggest that the MNX1-AS1/IGF2BP1 axis may serve as a potential biomarker and therapeutic target in NSCLC.Significance:MNX1-AS1 drives phase separation of IGF2BP1 to increase c-Myc and E2F1 signaling and to activate cell-cycle progression to promote proliferation in NSCLC.

The effect of MYLK-AS1 expression on gefitinib resistance of NSCLC.

MYLK-AS1 promotes TKI resistance of lung cancer by regulating GLUD1.

The quick rearrangement of ILF3 droplets. A time-lapse movie of droplets formed by ILF3 undergoes fusion event.

A list of top five potential MYLK-AS1-interacting protein candidates in PC9/GR cells based on RNA-protein pull-down assays and mass spectrometry analysis.