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 1

SETD1A promotes HCC stemness in vitro and in vivo.

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SETD1A promotes HCC stemness in vitro and in vivo. (A) Schematic outline...
(A) Schematic outline of CRISPR/Cas9 knockout screen. (B) A scatter plot of the gRNA distribution from the GeCKO screen. The TrxG proteins are labeled in red, and the PcG proteins are labeled in blue. (C) GO enrichment analysis of the hits promoting liver CSCs’ expansion. (D) Enrichment of the gRNAs targeting SETD1A in the CD24–CD133– non-CSCs. (E) ATAC-Seq analysis of the accessibility of SETD1A locus in the CD24+CD133+ CSCs and CD24–CD133– non-CSCs. (F) qRT-PCR analysis of SETD1A expression in CD24+CD133+ CSCs and CD24–CD133– non-CSCs (n = 3). Comparison of the proportion of CD24+CD133+ CSCs (G) as well as EpCAM+ CSCs (H) in scramble control and SETD1A-knockdown HCC cells using flow cytometry (n = 3). (I) The spheroid formation assays showing the role of SETD1A in HCC stemness in vitro (n = 3). Scale bar represents 500 μm. (J) The images of tumors’ formation in NOD/SCID mice injected subcutaneously with the scramble control and shSETD1A HCC cells. (K) Extreme Limiting Dilution Analysis for comparing the scramble control group and shSETD1A group. (L) Overall survival curves of mice transplanted with the scramble control and shSETD1A HCC cells. Data are presented as mean ± SEM. Statistical analysis was performed by unpaired 2-tailed Student’s t test. **P < 0.01, and ***P < 0.001.