Related Experiment Video

Updated: Feb 5, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
07:25

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

13.9K

Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress

Niveditha Nerlakanti1,2, Jiqiang Yao3, Duy T Nguyen1,4

  • 1Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Molecular Cancer Therapeutics
|September 23, 2018
PubMed

Insights

Castration-resistant prostate cancers (CRPC) develop resistance through BRD4-HOXB13 reprogramming. Targeting this pathway with BET inhibitors halts tumor growth and offers new therapeutic strategies for advanced prostate cancer.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Androgen receptor (AR) antagonist resistance is a major challenge in treating castration-resistant prostate cancers (CRPC).
  • Understanding the mechanisms of AR antagonist resistance is crucial for developing effective therapies.
  • CRPC evasion of androgen deprivation therapies (ADT) requires further investigation.

Purpose of the Study:

  • To identify the key molecular mechanisms driving CRPC resistance to ADT.
  • To investigate the role of BRD4 and HOXB13 in epigenetic reprogramming and CRPC proliferation.
  • To evaluate the therapeutic potential of targeting the BRD4-HOXB13 axis.

Main Methods:

  • Investigated the BRD4-HOXB13 epigenetic reprogramming in CRPC.
  • Utilized genetic disruption of HOXB13 and pharmacological inhibition of BRD4.
  • Employed dual-activity BET bromodomain-kinase inhibitors.
  • Performed integrative transcriptome analysis of BRD4-HOXB13 targets.
  • Analyzed gene expression in CRPC cell lines, patient-derived CTCs, and metastatic CRPC (mCRPC) patient samples.

Main Results:

  • CRPCs utilize BRD4-HOXB13 epigenetic reprogramming for androgen-independent proliferation.
  • BRD4 epigenetically upregulates HOXB13 expression, driving CRPC growth.
  • Disrupting HOXB13 or inhibiting BRD4 with BET inhibitors induced apoptosis, inhibited proliferation and migration, and suppressed CRPC growth.
  • The BRD4-HOXB13 transcriptome includes a proproliferative gene network (HOTBIN10).
  • HOTBIN10 genes, including AURKB and MELK, are overexpressed in metastatic CRPC and correlate with HOXB13 in abiraterone-resistant patients.

Conclusions:

  • The BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant phenotype of CRPCs.
  • This pathway represents a core proproliferative network driving ADT resistance.
  • Dual-activity BET bromodomain-kinase inhibitors effectively target this network.
  • AURKB inhibitors may offer additional therapeutic benefits for high-risk HOXB13-positive mCRPC.

More Related Videos

Murine Prostate Micro-dissection and Surgical Castration08:49

Murine Prostate Micro-dissection and Surgical Castration

Published on: May 11, 2016

47.7K
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients12:13

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients

Published on: November 19, 2019

7.2K

Related Concept Videos

Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.0K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
15.1K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.8K
Acid Suppressive Drugs for Peptic Ulcer Disease: Proton Pump Inhibitors01:13

Acid Suppressive Drugs for Peptic Ulcer Disease: Proton Pump Inhibitors

Peptic ulcers, often induced by H. pylori infections or NSAID usage, arise from disruptions in the delicate balance of gastric acid production. Peptic ulcers stem from heightened gastric acid levels due to H. pylori infections or NSAID use. The protective mucus layer diminishes in the presence of these factors, allowing gastric acid to erode the stomach lining and form ulcers.
Gastric acid, a potent cocktail of hydrogen and chloride ions, is produced in specialized parietal cells within the...
958
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.9K
Prokaryotic Transcriptional Activators and Repressors01:58

Prokaryotic Transcriptional Activators and Repressors

The organization of prokaryotic genes in their genome is notably different from that of eukaryotes. Prokaryotic genes are organized, such that the genes for proteins involved in the same biochemical process or function are located together in groups. This group of genes, along with their regulatory elements, are collectively known as an operon. The functional genes in an operon are transcribed together to give a single strand of mRNA known as polycistronic mRNA.
Transcription of prokaryotic...
25.5K