Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, 02125, USA.
Department of Biology, University of Massachusetts Boston, Boston, MA, 02125, USA.
Nat Commun. 2024 Jun 8;15(1):4914. doi: 10.1038/s41467-024-49234-9.
FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity.
FOXA 家族蛋白作为先驱因子，重塑致密的染色质结构。FOXA1 对于雄激素受体 (AR) 在正常前列腺上皮细胞和前列腺癌 (PCa) 的腔型亚型中的染色质结合至关重要。最近的研究强调了 FOXA2 的出现是对 AR 信号抑制治疗的适应性反应。然而，FOXA1 到 FOXA2 转换在调节癌症谱系可塑性中的作用仍不清楚。我们的研究表明，FOXA2 在多种 AR 非依赖性 PCa 亚型中结合到不同类别的发育增强子，其结合取决于 LSD1。此外，我们揭示了 FOXA2 在染色质上与 JUN 合作，并促进谱系可塑性癌细胞中 AP-1 的转录重编程，从而促进细胞状态向多个谱系的转变。总的来说，我们的研究结果强调了 FOXA2 作为一个普遍的可塑性驱动因子的关键作用，它重新布线 AP-1 以诱导癌症细胞谱系可塑性所必需的差异转录重编程。
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