SETD1A drives stemness by reprogramming the epigenetic landscape in hepatocellular carcinoma stem cells
Jianxu Chen, Zhijie Xu, Hongbin Huang, Yao Tang, Hong Shan, Fei Xiao
Jianxu Chen, Zhijie Xu, Hongbin Huang, Yao Tang, Hong Shan, Fei Xiao
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Research Article Hepatology Oncology

SETD1A drives stemness by reprogramming the epigenetic landscape in hepatocellular carcinoma stem cells

Abstract

Cancer stem cells (CSCs) are responsible for tumor progression and recurrence. However, the mechanisms regulating hepatocellular carcinoma (HCC) stemness remain unclear. Applying a genome-scale CRISPR knockout screen, we identified that the H3K4 methyltransferase SETD1A and other members of Trithorax group proteins drive cancer stemness in HCC. SET domain containing 1A (SETD1A) was positively correlated with poor clinical outcome in patients with HCC. Combination of SETD1A and serum alpha fetoprotein substantially improved the accuracy of predicting HCC relapse. Mechanistically, SETD1A mediates transcriptional activation of various histone-modifying enzymes, facilitates deposition of trimethylated H3K4 (H3K4me3) and H3K27me3, and activates oncogenic enhancers and super-enhancers, leading to activation of oncogenes and inactivation of tumor suppressor genes simultaneously in liver CSCs. In addition, SETD1A cooperates with polyadenylate-binding protein cytoplasmic 1 to regulate H3K4me3 modification on oncogenes. Our data pinpoint SETD1A as a key epigenetic regulator driving HCC stemness and progression, highlighting the potential of SETD1A as a candidate target for HCC intervention and therapy.

Authors

Jianxu Chen, Zhijie Xu, Hongbin Huang, Yao Tang, Hong Shan, Fei Xiao

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Figure 3

SETD1A promotes HCC stemness and progression by regulating histone modification.

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SETD1A promotes HCC stemness and progression by regulating histone modif...
(A) Representative SETD1A, H3K4me3, and H3K27me3 CUT&Tag profiles in CD24+CD133+ CSCs at BMI1, ZIC2, SETD1A, and PDK4 loci. (B) GO enrichment analysis of SETD1A-regulated genes in CD24+CD133+ CSCs. (C) Representative SETD1A, H3K4me3, and H3K27me3 CUT&Tag profiles in CD24+CD133+ CSCs at EZ H2, SETD1B, KDM4A, KAT5, DOT1L, and KMT2D loci. (D) The changes of H3K4me3-marked genes (indicated as K4me3), H3K37me3-marked genes (indicated as K27me3), and bivalent genes (indicated as K4/K27me3) resulting from SETD1A knockdown. (E) Venn diagram of the binding sites of H3K4me3 and H3K27me3 in control and SETD1A-knockdown HCC. (F) GO enrichment analysis of the genes losing H3K4me3 and gaining H3K27me3 resulting from SETD1A knockdown. (G) PPI network analysis of the regulators losing H3K4me3 and gaining H3K27me3 upon SETD1A knockdown. (H) GO enrichment analysis for the genes gaining H3K4me3 and losing H3K27me3 upon SETD1A knockdown. (I) PPI network analysis of the regulators gaining H3K4me3 and losing H3K27me3 upon SETD1A knockdown. (J) Representative H3K27me3 CUT&Tag profiles in the control and SETD1A-knockdown CD24+CD133+ CSCs at KITLG and EPHA3 loci. The expression of KITLG and EPHA3 is shown on the right. (K) Representative H3K4me3 CUT&Tag profiles in control and SETD1A-knockdown CD24+CD133+ CSCs at NGFR and WNT7A loci. Their expression of NGFR and WNT7A is shown on the right (n = 3). Data are presented as mean ± SEM. Statistical analysis was performed by unpaired 2-tailed Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001.