Aberrant activation of Homeobox genes in human cancers has long been documented, whereas the mechanisms underlying remain largely obscure. Super-enhancers (SEs) act as key regulatory elements for both cell identity genes and cancer genes. Herein, we reported that SE-associated HOXB gene cluster represented a common feature of colorectal cancer (CRC) cell lines and multiple HOXB genes within this cluster were overexpressed in CRC. Among them, we found that HOXB8 was oncogenic and its activation in CRC was driven by SE instead of genetic alteration. We further demonstrated that the master transcription factor MYC preferentially occupied SEs over TEs (typical enhancers) and regulated HOXB8 transcription by binding to the active elements of its SE. HOXB8 silencing induced reversal of transcriptional signatures associated with malignant phenotypes of CRC. Mechanistically, HOXB8 interacted with a key metastasis regulator BACH1 and instigated BACH1-mediated transcriptional cascade by directly occupying and activating BACH1 gene transcription together with BACH1 itself. Lastly, the relevance of HOXB8 activation in clinical settings was strengthened by its close association with prognostic outcomes of CRC patients.
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RNA-seq and ChIP-seq data generated in this study have been deposited at the Gene Expression Omnibus (GEO) under accession code GSE121209.
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This work was supported by Shenzhen Commission of Science and Innovation Programs [JCYJ20170817101008912, JCYJ20170818143305472, JCYJ20160331114230843], National Key Projects of Research and Development of China [2016YFC0904600], Natural Science Foundation of Shenzhen University for Overseas High-Caliber Personnel , National Natural Science Foundation of China  and grant from Guangdong Health Committee [B2019104]. We thank technical support from Instrumental Analysis Center of Shenzhen University (Xili Campus), and thank Mr Shikang Liu, and Ms Danhong Qiu for technical assistance.
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Ying, Y., Wang, Y., Huang, X. et al. Oncogenic HOXB8 is driven by MYC-regulated super-enhancer and potentiates colorectal cancer invasiveness via BACH1. Oncogene 39, 1004–1017 (2020). https://doi.org/10.1038/s41388-019-1013-1