Genome-wide binding analysis unveils critical implication of B-Myb-mediated transactivation in cancers

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-09-03 DOI:10.7150/ijbs.92607
Chuntao Tao, Tao Liu, Zongrong Zhao, Xuanqi Dou, Xing Xia, Kailong Du, Xiaofeng Zuo, Yitao Wang, Tingting Wang, Youquan Bu
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Abstract

B-Myb, also known as MYB proto-oncogene like 2 (MYBL2), is an important transcription factor implicated in transcription regulation, cell cycle and tumorigenesis. However, the molecular mechanism underlying B-Myb-controlled transactivation in different cell contexts as well as its functional implication in cancers remains elusive. In this study, we have conducted a comprehensive genome-wide analysis of B-Myb binding sites in multiple immortalized or cancer cell lines and identified its critical target genes. The results revealed that B-Myb regulates a common set of core cell cycle genes and cell type-specific genes through collaboration with other important transcription factors (e.g. NFY and MuvB complex) and binding to cell type-invariant promoters and cell type-specific enhancers and super-enhancers. KIF2C, UBE2C and MYC were further validated as B-Myb target genes. Loss-of-function analysis demonstrated that KIF2C knockdown inhibited tumor cell growth both in vitro and in vivo, suppressed cell motility and cell cycle progression, accompanied with defects in microtubule organization and mitosis, strongly suggesting that KIF2C is a critical regulator of cancer cell growth and mitosis, and maintains high cancer cell motility ability and microtubule dynamics. Pan-cancer transcriptomic analysis revealed that the overexpression of both B-Myb and KIF2C presents as independent prognostic markers in various types of cancer. Notably, B-Myb associates with NFYB, binds to target gene promoters, enhancers and super-enhancers, and provokes a cascade of oncogenic gene expression profiles in cancers. Overall, our results highly suggest the critical implication of B-Myb-mediated gene regulation in cancers, and the promising therapeutic and prognostic potentials of B-Myb and KIF2C for cancer diagnosis and treatment.
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全基因组结合分析揭示了 B-Myb 介导的转录激活在癌症中的重要作用
B-Myb又称MYB原癌基因2(MYBL2),是一种重要的转录因子,与转录调控、细胞周期和肿瘤发生有关。然而,B-Myb 在不同细胞环境中控制转录活化的分子机制及其在癌症中的功能性影响仍未确定。在这项研究中,我们对多个永生细胞系或癌细胞系中的 B-Myb 结合位点进行了全面的全基因组分析,并确定了其关键靶基因。结果发现,B-Myb通过与其他重要转录因子(如NFY和MuvB复合物)合作,并与细胞类型不变的启动子和细胞类型特异的增强子和超级增强子结合,调控一组常见的核心细胞周期基因和细胞类型特异基因。KIF2C、UBE2C 和 MYC 进一步被验证为 B-Myb 的靶基因。功能缺失分析表明,KIF2C敲除可抑制体外和体内肿瘤细胞的生长,抑制细胞运动和细胞周期的进展,并伴有微管组织和有丝分裂的缺陷。泛癌症转录组学分析表明,B-Myb和KIF2C的过表达是各类癌症的独立预后标志。值得注意的是,B-Myb与NFYB结合,与靶基因启动子、增强子和超增强子结合,并在癌症中引发一连串的致癌基因表达谱。总之,我们的研究结果高度揭示了 B-Myb 介导的基因调控在癌症中的关键作用,以及 B-Myb 和 KIF2C 在癌症诊断和治疗中的治疗和预后潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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