Transcriptional network involving ERG and AR orchestrates Distal-less homeobox-1 mediated prostate cancer progression

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 similar to 60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, similar to 96% of TMPRSS2-ERG fusion-positive and similar to 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.

Automated summary

DLX1 serves as a crucial factor in prostate cancer, and its high levels are associated with aggressive disease and poor prognosis. Through regulating the transcriptional activity of DLX1, ERG and AR contribute to tumorigenesis and metastasis. Inhibiting ERG/AR-mediated transcription of DLX1 using BET inhibitors and anti-androgens can reduce its expression and downstream oncogenic effects.