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Oncogenic HOXB8 is driven by MYC-regulated super-enhancer and potentiates colorectal cancer invasiveness via BACH1.
Oncogene ( IF 6.9 ) Pub Date : 2019-10-07 , DOI: 10.1038/s41388-019-1013-1 Ying Ying 1 , Yejun Wang 1 , Xiaoyan Huang 1 , Yanmei Sun 1 , Junbao Zhang 1 , Meiqi Li 1 , Junhui Zeng 1 , Maolin Wang 1 , Wenjun Xiao 1 , Lan Zhong 2 , Bo Xu 3 , Lili Li 4 , Qian Tao 4 , Xiaomei Wang 1 , Xing-Sheng Shu 1
Oncogene ( IF 6.9 ) Pub Date : 2019-10-07 , DOI: 10.1038/s41388-019-1013-1 Ying Ying 1 , Yejun Wang 1 , Xiaoyan Huang 1 , Yanmei Sun 1 , Junbao Zhang 1 , Meiqi Li 1 , Junhui Zeng 1 , Maolin Wang 1 , Wenjun Xiao 1 , Lan Zhong 2 , Bo Xu 3 , Lili Li 4 , Qian Tao 4 , Xiaomei Wang 1 , Xing-Sheng Shu 1
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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.
中文翻译：
致癌HOXB8由MYC调节的超级增强剂驱动，并通过BACH1增强结直肠癌的侵袭性。
长期以来已有文献记载人类癌症中Homeobox基因的异常激活，但其潜在机制仍不清楚。超级增强子（SE）是细胞身份基因和癌症基因的关键调控元件。在本文中，我们报道了SE相关的HOXB基因簇代表结直肠癌（CRC）细胞系的共同特征，并且该簇中的多个HOXB基因在CRC中过表达。其中，我们发现HOXB8是致癌的，其在CRC中的激活是由SE驱动的，而不是遗传改变。我们进一步证明，主转录因子MYC比SE（典型增强子）优先占据SE，并通过与其SE的活性元件结合来调节HOXB8转录。HOXB8沉默诱导逆转与CRC恶性表型相关的转录特征。从机制上讲，HOXB8与关键的转移调节因子BACH1相互作用，并通过直接占据和激活BACH1基因转录以及BACH1自身来促进BACH1介导的转录级联反应。最后，HOXB8激活与CRC患者的预后密切相关，进一步增强了HOXB8激活在临床中的相关性。
更新日期：2019-10-08
中文翻译：
致癌HOXB8由MYC调节的超级增强剂驱动，并通过BACH1增强结直肠癌的侵袭性。
长期以来已有文献记载人类癌症中Homeobox基因的异常激活，但其潜在机制仍不清楚。超级增强子（SE）是细胞身份基因和癌症基因的关键调控元件。在本文中，我们报道了SE相关的HOXB基因簇代表结直肠癌（CRC）细胞系的共同特征，并且该簇中的多个HOXB基因在CRC中过表达。其中，我们发现HOXB8是致癌的，其在CRC中的激活是由SE驱动的，而不是遗传改变。我们进一步证明，主转录因子MYC比SE（典型增强子）优先占据SE，并通过与其SE的活性元件结合来调节HOXB8转录。HOXB8沉默诱导逆转与CRC恶性表型相关的转录特征。从机制上讲，HOXB8与关键的转移调节因子BACH1相互作用，并通过直接占据和激活BACH1基因转录以及BACH1自身来促进BACH1介导的转录级联反应。最后，HOXB8激活与CRC患者的预后密切相关，进一步增强了HOXB8激活在临床中的相关性。
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