The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome in prostate cancer. Together, these studies reveal new mechanisms by which RB loss induces cancer progression and highlight the importance of understanding the targets of E2F1 function. Significance: This study identifies that RB loss in prostate cancer drives cooperation between AR and E2F1 as coregulators of transcription, which is linked to the progression of advanced disease.

中文翻译：

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RB 缺陷型癌症中的新型致癌转录因子协同作用


视网膜母细胞瘤肿瘤抑制因子 (RB) 是 E2F 依赖性转录的关键调节因子，控制着多种促肿瘤发生网络，包括但不限于细胞周期控制。在这里，在前列腺癌等基因模型中 RB 丢失后对 E2F1 功能进行全基因组评估，揭示了与致癌转录因子（包括疾病进展的主要驱动因素雄激素受体 (AR)）意外的重新定位和合作。进一步的研究表明，观察到的 AR/E2F1 合作引发了促进癌症表型的新型转录网络，特别是与逃避细胞死亡相关的转录网络。这些观察结果反映在人类疾病的评估中，表明 AR/E2F1 cooperome 在前列腺癌中的临床相关性。总之，这些研究揭示了 RB 丢失诱导癌症进展的新机制，并强调了了解 E2F1 功能靶点的重要性。意义：这项研究发现，前列腺癌中的 RB 缺失会驱动 AR 和 E2F1 作为转录共调节因子之间的合作，这与晚期疾病的进展有关。