2. Academic Validation
  3. Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer

  • Prostate. 2023 Aug 11. doi: 10.1002/pros.24603.
Bin Fu 1,  Liyang Wang 2 3,  Tianwei Jia 4 5 6,  Zhao Wei 7,  Nuosu Nama 2 8,  Jiaqian Liang 9,  Xinghua Liao 10,  XiaMing Liu 11,  Yanfei Gao 12,  Xiaoqiang Liu 1,  Raymond S Mao 13,  Keshan Wang 13 14,  Ju Guo 1,  Shaoyong S Chen 1 2
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R.China.
  • 2 Department of Medicine, Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachussetts, USA.
  • 3 Department of Cell Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, ShaanXi, P.R.China.
  • 4 Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R.China.
  • 5 Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, Shandong, P.R.China.
  • 6 Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, Shandong, P.R.China.
  • 7 Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, P.R.China.
  • 8 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
  • 9 Department of Urology, Wuhan No.1 Hospital, Wuhan, P.R.China.
  • 10 Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, WuHan, Hubei, P.R.China.
  • 11 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China.
  • 12 Center for Medical Epigenetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, P.R.China.
  • 13 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 14 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PMID: 37565264 DOI: 10.1002/pros.24603
Abstract

Background: The discovery of Androgen Receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region.

Methods: RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites.

Results: In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via Epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate Cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site.

Conclusion: Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

Keywords

MYC; androgen receptor; dual functions; equilibration; prostate cancer; transcriptional circuitry.

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