Oncogenic HOXB8 is driven by MYC-regulated super-enhancer and potentiates colorectal cancer invasiveness via BACH1

Ying, Ying; Wang, Yejun; Huang, Xiaoyan; Sun, Yanmei; Zhang, Junbao; Li, Meiqi; Zeng, Junhui; Wang, Maolin; Xiao, Wenjun; Zhong, Li-Ye; Xu, Bo; Li, Lili; Tao, Qian; Wang, Xiaomei; Shu, Xing-sheng

doi:10.1038/s41388-019-1013-1

Cited by 53 publications

(85 citation statements)

References 44 publications

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“…Moreover, manipulating the rs9303542 region could change the expression of HOXB genes especially for HOXB7 and HOXB8. We also observed upregulated expression of HOXB7 and HOXB8 in EOC tumor samples as well as the association between HOXB7 and HOXB8 expression and overall survival for EOC patients, the results are consistent with previous findings for HOXB7 and HOXB8 in various human cancers including ovarian cancer (Errico et al, 2016;Monterisi et al, 2018;Chen et al, 2020;Ying et al, 2020). Even though, with strong evidence from HiChIP results and validation results, no significant eQTL associations were found between rs9303542 and the expression of HOXB7 (Supplementary Figure 5A) or HOXB8 (Supplementary Figure 5B).…”

Section: Discussionsupporting

confidence: 91%

Functional Interrogation of Enhancer Connectome Prioritizes Candidate Target Genes at Ovarian Cancer Susceptibility Loci

et al. 2021

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Identifying causal regulatory variants and their target genes from the majority of non-coding disease-associated genetic loci is the main challenge in post-Genome-Wide Association Studies (GWAS) functional studies. Although chromosome conformation capture (3C) and its derivative technologies have been successfully applied to nominate putative causal genes for non-coding variants, many GWAS target genes have not been identified yet. This study generated a high-resolution contact map from epithelial ovarian cancer (EOC) cells with two H3K27ac-HiChIP libraries and analyzed the underlying gene networks for 15 risk loci identified from the largest EOC GWAS. By combinatory analysis of 4,021 fine-mapped credible variants of EOC GWAS and high-resolution contact map, we obtained 162 target genes that mainly enriched in cancer related pathways. Compared with GTEx eQTL genes in ovarian tissue and annotated proximal genes, 132 HiChIP targets were first identified for EOC causal variants. More than half of the credible variants (CVs) involved interactions that were over 185 kb in distance, indicating that long-range transcriptional regulation is an important mechanism for the function of GWAS variants in EOC. We also found that many HiChIP gene targets showed significantly differential expressions between normal ovarian and EOC tumor samples. We validated one of these targets by manipulating the rs9303542 located region with CRISPR-Cas9 deletion and dCas9-VP64 activation experiments and found altered expression of HOXB7 and HOXB8 at 17q21.32. This study presents a systematic analysis to identify putative target genes for causal variants of EOC, providing an in-depth investigation of the mechanisms of non-coding regulatory variants in the etiology and pathogenesis of ovarian cancer.

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Section: Discussionsupporting

confidence: 91%

Functional Interrogation of Enhancer Connectome Prioritizes Candidate Target Genes at Ovarian Cancer Susceptibility Loci

et al. 2021

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“…ChIP-seq experiments were essentially carried out as described before 46 with modification in spike-in normalization. Briefly, a constant amount (about 5% of total chromatin) of chromatin from a foreign species (mouse intestine in our case) to each ChIP reaction before the immunoprecipitation step to normalize potential bias introduced by experiment and/or data processing procedures between different reactions, which could improve the power and accuracy of quantitative comparison of ChIP-seq signals 47 .…”

Section: Methodsmentioning

confidence: 99%

Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer

Zhang¹,

Ying²,

Li³

et al. 2020

Theranostics

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Tumor-initiating cells (TICs) maintain heterogeneity within tumors and seed metastases at distant sites, contributing to therapeutic resistance and disease recurrence. In colorectal cancer (CRC), strategy that effectively eradicates TICs and is of potential value for clinical use still remains in need. Methods : The anti-tumorigenic activity of a small-molecule inhibitor of KDM6 histone demethylases named GSK-J4 in CRC was evaluated by in vitro assays and in vivo imaging of xenografted tumors. Sphere formation, flow cytometry analysis of cell surface markers and intestinal organoid formation were performed to examine the impact of GSK-J4 on TIC properties. Transcriptome analysis and global profiling of H3K27ac, H3K27me3, and KDM6A levels by ChIP-seq were conducted to elucidate how KDM6 inhibition reshapes epigenetic landscape and thereby eliminating TICs. Results : GSK-J4 alleviated the malignant phenotypes of CRC cells in vitro and in vivo , sensitized them to chemotherapeutic treatment, and strongly repressed TIC properties and stemness-associated gene signatures in these cells. Mechanistically, KDM6 inhibition induced global enhancer reprogramming with a preferential impact on super-enhancer-associated genes, including some key genes that control stemness in CRC such as ID1 . Besides, expression of both Kdm6a and Kdm6b was more abundant in mouse intestinal crypt when compared with upper villus and inhibition of their activities blocked intestinal organoid formation. Finally, we unveiled the power of KDM6B in predicting both the overall survival outcome and recurrence of CRC patients. Conclusions : Our study provides a novel rational strategy to eradicate TICs through reshaping epigenetic landscape in CRC, which might also be beneficial for optimizing current therapeutics.

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“…Recently, accumulating evidence indicated that BACH1 is highly expressed in many solid tumors. Aberrant expression of BACH1 contributes to tumor metastasis in breast cancer, 7‐9 colorectal cancer, 10‐13 prostate cancer, 14 ovarian cancer, 15,16 pancreatic cancer, 17 osteosarcoma, 18 and lung cancer 19,20 . Mechanistically, some of the studies revealed that BACH1 functions as a master transcriptional regulator of cancer progression and metastasis.…”

Section: Introductionmentioning

confidence: 99%

BACH1 promotes the progression of esophageal squamous cell carcinoma by inducing the epithelial–mesenchymal transition and angiogenesis

et al. 2021

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Metastasis to regional lymph nodes or distal organs predicts the progression of the disease and poor prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies demonstrated that BTB and CNC homology 1 (BACH1) participates in various types of tumor metastasis. However, the function of BACH1 in ESCC was rarely reported. The present study demonstrated that BACH1 protein was overexpressed in ESCC tissues compared with paired esophageal epithelial tissues according to immunohistochemical staining (IHC). Higher levels of BACH1 mRNA were associated with decreased overall survival (OS) and shorter disease‐free survival (DFS) of ESCC patients based on an analysis of The Cancer Genome Atlas (TCGA) datasets. BACH1 significantly enhanced the migration and invasion of ESCC in vitro. Mechanistically, BACH1 promoted the epithelial–mesenchymal transition (EMT) by directly activating the transcription of CDH2, SNAI2, and VIM, as determined by chromatin immunoprecipitation‐quantitative polymerase chain reaction (ChIP‐qPCR). BACH1 overexpression significantly enhanced CDH2 promoter activity according to the results of a luciferase assay. The results of subsequent experiments indicated that BACH1 enhanced the growth of tumor xenografts. The density of CD31+ blood vessels and the expression of vascular endothelial growth factor C (VEGFC) in tumor xenografts were significantly associated with BACH1 levels according to the results of IHC and immunofluorescence (IF) analyses performed in vivo. Moreover, ChIP‐qPCR analysis demonstrated that the transcriptional activity of VEGFC was also upregulated by BACH1. Thus, BACH1 contributes to ESCC metastasis and tumorigenesis by partially facilitating the EMT and angiogenesis, and BACH1 may be a promising therapeutic target or molecular marker in ESCC.

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Oncogenic HOXB8 is driven by MYC-regulated super-enhancer and potentiates colorectal cancer invasiveness via BACH1

Cited by 53 publications

References 44 publications

Functional Interrogation of Enhancer Connectome Prioritizes Candidate Target Genes at Ovarian Cancer Susceptibility Loci

Functional Interrogation of Enhancer Connectome Prioritizes Candidate Target Genes at Ovarian Cancer Susceptibility Loci

Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer

BACH1 promotes the progression of esophageal squamous cell carcinoma by inducing the epithelial–mesenchymal transition and angiogenesis

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