Bromodomain containing protein 4 (BRD4) plays a critical role in controlling the expression of genes involved in development and cancer. Inactivation of BRD4 inhibits cancer growth, making it a promising anticancer drug target. The cancer stem cell (CSC) population is a key driver of recurrence and metastasis in patients with cancer. Here we show that cancer stem-like cells can be enriched from squamous cell carcinomas (SCC), and that these cells display an aggressive phenotype with enhanced stem cell marker expression, migration, invasion, and tumor growth. BRD4 is highly elevated in this aggressive subpopulation of cells, and its function is critical for these CSC-like properties. Moreover, BRD4 regulates ΔNp63α, a key transcription factor that is essential for epithelial stem cell function that is often overexpressed in cancers. BRD4 regulates an EZH2/STAT3 complex that leads to increased ΔNp63α-mediated transcription. Targeting BRD4 in human SCC reduces ΔNp63α, leading to inhibition of spheroid formation, migration, invasion, and tumor growth. These studies identify a novel BRD4-regulated signaling network in a subpopulation of cancer stem-like cells, elucidating a possible avenue for effective therapeutic intervention. Significance: This study identifies a signaling cascade driven by BRD4 that upregulates ΔNp63α to promote cancer stem-like properties, which has potential therapeutic implications for the treatment of squamous cell carcinomas.

中文翻译：

---

BRD4 调节转录因子 {Delta}Np63{alpha} 以驱动鳞状细胞癌中的癌症干细胞表型

Bromodomain containing protein 4 (BRD4) 在控制发育和癌症相关基因的表达方面起着关键作用。BRD4 的失活会抑制癌症的生长，使其成为有前途的抗癌药物靶点。癌症干细胞 (CSC) 群体是癌症患者复发和转移的关键驱动因素。在这里，我们表明癌症干细胞样细胞可以从鳞状细胞癌 (SCC) 中富集，并且这些细胞显示出具有增强的干细胞标记物表达、迁移、侵袭和肿瘤生长的侵袭性表型。BRD4 在这种侵袭性细胞亚群中高度升高，其功能对于这些 CSC 样特性至关重要。此外，BRD4 调节 ΔNp63α，这是一种关键转录因子，对于通常在癌症中过度表达的上皮干细胞功能至关重要。BRD4 调节 EZH2/STAT3 复合物，导致 ΔNp63α 介导的转录增加。在人类 SCC 中靶向 BRD4 可减少 ΔNp63α，从而抑制球体形成、迁移、侵袭和肿瘤生长。这些研究在癌症干细胞样细胞亚群中发现了一个新的 BRD4 调节信号网络，阐明了有效治疗干预的可能途径。意义：这项研究确定了一个由 BRD4 驱动的信号级联，它上调 ΔNp63α 以促进癌症干细胞样特性，这对鳞状细胞癌的治疗具有潜在的治疗意义。这些研究在癌症干细胞样细胞亚群中发现了一个新的 BRD4 调节信号网络，阐明了有效治疗干预的可能途径。意义：这项研究确定了一个由 BRD4 驱动的信号级联，它上调 ΔNp63α 以促进癌症干细胞样特性，这对鳞状细胞癌的治疗具有潜在的治疗意义。这些研究在癌症干细胞样细胞亚群中发现了一个新的 BRD4 调节信号网络，阐明了有效治疗干预的可能途径。意义：这项研究确定了一个由 BRD4 驱动的信号级联，它上调 ΔNp63α 以促进癌症干细胞样特性，这对鳞状细胞癌的治疗具有潜在的治疗意义。