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

Autor: Ying Y; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Wang Y; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Huang X; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Sun Y; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Zhang J; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Li M; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Zeng J; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Wang M; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Xiao W; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Zhong L; Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, 610041, Chengdu, China., Xu B; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300070, Tianjin, China., Li L; Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer, The Chinese University of Hong Kong, 00000, Hong Kong, China., Tao Q; Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer, The Chinese University of Hong Kong, 00000, Hong Kong, China., Wang X; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Shu XS; Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, 518060, Shenzhen, China. shu@szu.edu.cn.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2020 Jan; Vol. 39 (5), pp. 1004-1017. Date of Electronic Publication: 2019 Oct 07.
DOI: 10.1038/s41388-019-1013-1
Abstrakt: 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.
Databáze: MEDLINE
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