Related Experiment Video

Updated: Dec 10, 2025

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
12:13

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

Published on: November 19, 2019

7.1K

ACK1-AR and AR-HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers

Eric H Kim1,2,3, Dengfeng Cao3,4, Nupam P Mahajan1,2,3

  • 1Division of Urologic Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.

NAR Cancer
|September 5, 2020
PubMed

Insights

Prostate cancer (PC) resistance to anti-androgens involves androgen receptor (AR) co-regulators ACK1 and HOXB13. Targeting ACK1 with (R)-9b may overcome resistance by disrupting these survival pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Androgen receptor (AR) is crucial in prostate cancer (PC) pathogenesis.
  • AR activity relies on co-regulators, with fluctuating dependence on androgen availability.
  • Castration-resistant PCs (CRPCs) increasingly depend on ACK1 and HOXB13 pathways for survival.

Purpose of the Study:

  • To elucidate the roles of ACK1 and HOXB13 in CRPC pathogenesis and anti-androgen resistance.
  • To investigate the crosstalk between AR, ACK1, and HOXB13 pathways in CRPC recurrence.
  • To evaluate the potential of targeting ACK1 for CRPC treatment.

Main Methods:

  • Analysis of AR co-regulator interactions in PC models.
  • Investigating ACK1-mediated phosphorylation of histone H4 and its effect on AR expression.
  • Examining the role of BRD4 in HOXB13 gene expression and AR-V7 recruitment.
  • Assessing the efficacy of the ACK1 inhibitor (R)-9b in CRPC models.

Main Results:

  • Androgen depletion enhances CRPC dependence on ACK1 and HOXB13.
  • ACK1 phosphorylates histone H4, epigenetically upregulating AR and conferring anti-androgen resistance.
  • (R)-9b, an ACK1 inhibitor, targets this resistance mechanism.
  • BRD4 upregulates HOXB13, which activates MYC targets (AURKA/AURKB) and facilitates AR-V7 recruitment.
  • Crosstalk between AR-ACK1 and AR-HOXB13 pathways drives CRPC recurrence.

Conclusions:

  • ACK1 and HOXB13 are key mediators of CRPC recurrence and resistance.
  • Targeting ACK1 with (R)-9b offers a potential therapeutic strategy for CRPC.
  • Understanding AR co-regulator pathways is critical for overcoming treatment resistance in prostate cancer.

More Related Videos

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture10:38

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture

Published on: November 22, 2019

9.4K
Murine Prostate Micro-dissection and Surgical Castration08:49

Murine Prostate Micro-dissection and Surgical Castration

Published on: May 11, 2016

47.0K

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
11.1K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.6K
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
33.0K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.0K
Hedgehog Signaling Pathway02:33

Hedgehog Signaling Pathway

The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
9.3K
Lethal Alleles02:41

Lethal Alleles

Agouti: A Lethal Allele
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
17.4K