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<p>Yin Yang 1 (YY1) is a key transcription factor that drives prostate cancer (PCa) progression through bidirectional transcriptional regulation. Clinically, high expression of YY1 and abnormal cytoplasmic aggregation in PCa tissues are significantly associated with aggressive clinical-pathological features. These patterns hold important diagnostic and prognostic value at the tissue level, serving as promising histopathological biomarkers for assessing tumor invasiveness and therapeutic resistance. Mechanistically, YY1 drives PCa progression through multifaceted networks: it transcriptionally activates oncogenes such as Krüppel-like factor 4 (KLF4) and Prostate Specific Antigen (PSA); epigenetically induces EMT via Twist1/hnRNPM and stimulates YAP/TAZ signaling through the DNAH8AS1/miR-186-5p axis; promotes metabolic reprogramming by synergizing with BRD2/4 to activate PFKP and facilitating hypoxia adaptation via phase separation with HIF-1α; and contributes to immunosuppression by polarizing M2 macrophages and upregulating PD-L1 through IL-4/STAT6, thereby inhibiting CD8⁺ T cells. YY1 also sustains prostate cancer stem cells (PCSCs) self-renewal and chemoresistance via SOX2/BMI1. Targeting strategies for YY1 include small-molecule inhibitors (e.g.,Tenapanor), epigenetic drugs (e.g., Entecavir), gene editing, and immune combination therapies. By disrupting interactions between YY1 and HIF-1α/HDAC1/BRD4 or reversing immune suppression and metabolic adaptation, these approaches significantly inhibit tumor progression. This review systematically outlines the multidimensional regulatory mechanisms and therapeutic targeting of YY1 in PCa, offering a foundation for precision transcription factor intervention.</p>

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YY1 in prostate cancer: multidimensional oncogenicmechanisms and emerging therapeutic vulnerabilities

  • 期刊论文

  • 发表日期：

    2026年1月7日

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  • Qiuyu Liu,
  • Zhongxiu Liang,
  • Lu Li,
  • Ruyan Wen,
  • Linjian Mo,
  • Yonghong Liu,
  • Xueni Wang

摘要

Yin Yang 1 (YY1) is a key transcription factor that drives prostate cancer (PCa) progression through bidirectional transcriptional regulation. Clinically, high expression of YY1 and abnormal cytoplasmic aggregation in PCa tissues are significantly associated with aggressive clinical-pathological features. These patterns hold important diagnostic and prognostic value at the tissue level, serving as promising histopathological biomarkers for assessing tumor invasiveness and therapeutic resistance. Mechanistically, YY1 drives PCa progression through multifaceted networks: it transcriptionally activates oncogenes such as Krüppel-like factor 4 (KLF4) and Prostate Specific Antigen (PSA); epigenetically induces EMT via Twist1/hnRNPM and stimulates YAP/TAZ signaling through the DNAH8AS1/miR-186-5p axis; promotes metabolic reprogramming by synergizing with BRD2/4 to activate PFKP and facilitating hypoxia adaptation via phase separation with HIF-1α; and contributes to immunosuppression by polarizing M2 macrophages and upregulating PD-L1 through IL-4/STAT6, thereby inhibiting CD8⁺ T cells. YY1 also sustains prostate cancer stem cells (PCSCs) self-renewal and chemoresistance via SOX2/BMI1. Targeting strategies for YY1 include small-molecule inhibitors (e.g.,Tenapanor), epigenetic drugs (e.g., Entecavir), gene editing, and immune combination therapies. By disrupting interactions between YY1 and HIF-1α/HDAC1/BRD4 or reversing immune suppression and metabolic adaptation, these approaches significantly inhibit tumor progression. This review systematically outlines the multidimensional regulatory mechanisms and therapeutic targeting of YY1 in PCa, offering a foundation for precision transcription factor intervention.