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

Sakshi Goel, Vipul Bhatia, Sushmita Kundu, Tanay Biswas, Shannon Carskadon, Nilesh Gupta, Mohammad Asim, Colm Morrissey, Nallasivam Palanisamy and Bushra Ateeq ()
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Sakshi Goel: Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur
Vipul Bhatia: Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur
Sushmita Kundu: Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur
Tanay Biswas: Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur
Shannon Carskadon: Vattikuti Urology Institute, Department of Urology, Henry Ford Health System
Nilesh Gupta: Henry Ford Health System
Mohammad Asim: Faculty of Health and Medical Sciences, University of Surrey
Colm Morrissey: University of Washington
Nallasivam Palanisamy: Vattikuti Urology Institute, Department of Urology, Henry Ford Health System
Bushra Ateeq: Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25623-2

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