B-Myb，也称为 MYB 原癌基因样 2 (MYBL2)，是一种重要的转录因子，参与转录调控、细胞周期和肿瘤发生。然而，不同细胞环境中 B-Myb 控制的反式激活的分子机制及其在癌症中的功能意义仍然难以捉摸。在这项研究中，我们对多个永生化或癌细胞系中的 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。结果表明，B-Myb 通过与其他重要转录因子（例如 NFY 和 MuvB 复合体）协作并与细胞类型不变启动子和细胞类型特异性增强子结合来调节一组共同的核心细胞周期基因和细胞类型特异性基因和超级增强剂。 KIF2C、UBE2C 和 MYC 被进一步验证为 B-Myb 靶基因。功能丧失分析表明，KIF2C 敲低在体外和体内均抑制肿瘤细胞生长，抑制细胞运动和细胞周期进展，并伴有微管组织和有丝分裂缺陷，强烈表明 KIF2C 是癌细胞生长的关键调节因子和有丝分裂，并保持较高的癌细胞运动能力和微管动力学。泛癌转录组分析表明，B-Myb 和 KIF2C 的过度表达在各种类型的癌症中都是独立的预后标志物。值得注意的是，B-Myb 与 NFYB 结合，与靶基因启动子、增强子和超级增强子结合，并引发癌症中一系列致癌基因表达谱。总体而言，我们的结果高度表明 B-Myb 介导的基因调控在癌症中的重要意义，以及 B-Myb 和 KIF2C 在癌症诊断和治疗方面的有前景的治疗和预后潜力。© 作者。

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.© The author(s).