Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, U.P., India.
Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, USA.
Nat Commun. 2021 Sep 7;12(1):5325. doi: 10.1038/s41467-021-25623-2.
Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, ~96% of TMPRSS2-ERG fusion-positive and ~70% of androgen receptor (AR)-positive patients show elevated DLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation of DLX1 in ERG-positive background. However, in ERG-negative context, AR/AR-V7 and FOXA1 suffice to upregulate DLX1. Notably, inhibiting ERG/AR-mediated DLX1 transcription using BET inhibitor (BETi) or/and anti-androgen drugs reduce its expression and downstream oncogenic effects. Conclusively, this study establishes DLX1 as a direct-target of ERG/AR with an oncogenic role and demonstrates the clinical significance of BETi and anti-androgens for DLX1-positive patients.
远端同源盒转录因子 1（DLX1）是一种被广泛认可的前列腺癌（PCa）诊断的非侵入性生物标志物，但其在疾病发病机制中的作用机制尚不清楚。在这里，我们揭示了 DLX1 的致癌作用，并表明阻断其功能会导致肿瘤发生和转移减少。我们观察到，约 60%的晚期和转移性患者显示出更高的 DLX1 水平。此外，约 96%的 TMPRSS2-ERG 融合阳性和约 70%的雄激素受体（AR）阳性患者显示出升高的 DLX1，与侵袭性疾病和不良预后相关。从机制上讲，ERG 与增强子结合的 AR 和 FOXA1 协调，以驱动 ERG 阳性背景下 DLX1 的转录上调。然而，在 ERG 阴性情况下，AR/AR-V7 和 FOXA1 足以上调 DLX1。值得注意的是，使用 BET 抑制剂（BETi）和/或抗雄激素药物抑制 ERG/AR 介导的 DLX1 转录可降低其表达及其下游致癌作用。总之，这项研究确立了 DLX1 作为 ERG/AR 的直接靶标，具有致癌作用，并证明了 BETi 和抗雄激素药物对 DLX1 阳性患者的临床意义。
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