Metastases are a primary cause of cancer-associated mortality; however, the mechanisms underlying aggressive progression have not been clearly elucidated. Genome-wide features of chromatin accessibility through ATAC-seq from HCC primary and metastatic tumors revealed that many distal regulatory elements spreading the genome become accessible during aggressive progression, the changes of which are associated with NFY-family. And NFYB is frequently upregulated in tumor with metastasis. Mechanistically, LINC01137 recruits SMYD3 to enhance H3K4me3 occupancy at IL-1 β , CXCL2 and CCL20 promoters by inhibiting lysine ubiquitination to stabilize NFYB, which in turn upregulates IL-1 β , CXCL2 and CCL20. HCC-derived cytokine transforms macrophages to the M2 phenotype to foster an inhibitory tumor microenvironment and anti-PDL1 tolerance. Importantly, LINC01137 transcription is activated by the NFYB/KAT2B complex in a feed-forward loop. Notably, treatment with an IL-1 β inhibitor enhances the blockade efficacy of PD-L1 in NFYB-overexpressing HCC. Our findings imply an immunosuppressive role of NFYB–LINC01137 signaling during aggressive HCC progression and support the concept of microenvironment engineering in immunotherapy.
Zhou et al. (Sun,) studied this question.