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Prostate Cancer: The Role of Androgen Receptor and RARγ

Researchers investigate how RARγ and miR-96 affect prostate cancer treatment resistance.

― 6 min read


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Prostate cancer (PCa) is a serious disease that affects many men, especially as they get older. One treatment involves using drugs that block signals from hormones like androgens, which can help control cancer for a while. However, many patients experience a return of the cancer, which can be harder to treat the second time around. Researchers are trying to understand why this happens, especially with the role of the Androgen Receptor (AR) in these processes.

The Role of Androgen Receptor in Prostate Cancer

The androgen receptor is a protein that helps cells respond to androgens, the male hormones like testosterone. In normal prostate cells, the AR is important for growth and survival. However, in advanced prostate cancer, the AR can sometimes switch its function. This switch may lead to cell growth rather than normal cell behavior, allowing the cancer to thrive and spread. Some cancer cells change their characteristics to become more aggressive and resistant to treatments.

Mechanisms of Treatment Resistance

When prostate cancer becomes resistant to treatment, it often involves changes in how the AR works. This can include modifications to the AR or changes in its interaction with other proteins. One area of study is the role of another protein called RARγ (retinoic acid receptor gamma). RARγ can interact with the AR and may help maintain the normal functions of prostate cells.

Researchers are particularly interested in how the RARγ protein might help restore normal cell behavior in prostate cancer. By studying the RARγ complex and its role in AR function, scientists hope to find new ways to treat patients with advanced prostate cancer.

The Complex Interactions Between Proteins

The interaction between RARγ and AR is complex. Various proteins work together with both RARγ and AR in a network. When prostate cancer is present, these interactions can change, affecting how cells grow and respond to treatment. While the AR usually promotes healthy prostate cell functions, changes in these interactions can lead to cancer progression.

Targeting Treatment Resistance

To combat treatment resistance, scientists are looking for new strategies. One approach is to target components involved in cell growth and differentiation. By understanding which proteins are important for these processes, researchers could potentially steer cancer cells back toward more normal behavior.

A key goal is to develop treatments that can restore the normal functions of the AR while reducing the aggressive traits of cancer cells. This may include therapies that enhance the activity of RARγ or manipulate its interactions with AR.

The Role of MicroRNA

MicroRNAs (MiRNAs) are small RNA molecules that can regulate Gene Expression. One specific miRNA, miR-96, has been linked to the regulation of RARγ and AR. In prostate cancer, changes in miR-96 expression may contribute to the treatment resistance seen in many patients.

When miR-96 levels are high, it can target important proteins involved in prostate cell behavior, including RARγ and AR. This can lead to alterations in how these proteins function, making cancer cells more aggressive. Conversely, reducing the levels of miR-96 may help restore normal functions to these proteins.

Research Focus

To understand the role of the RARγ complex in advanced prostate cancer, researchers have looked at how RARγ interacts with AR and other proteins. They have used various scientific techniques to identify how these interactions change in different models of prostate cancer.

1. Protein Interaction Studies

One method used is known as proteomics, which studies all the proteins present in a cell. By examining these proteins, researchers can identify how RARγ and AR interact in both healthy and cancerous conditions. This helps to reveal the complex relationships between AR, RARγ, and other important proteins.

2. Gene Expression Analysis

In addition to studying proteins, researchers also analyze gene expression in prostate cancer cells. This involves determining which genes are turned on or off in different conditions, such as when treated with drugs. Understanding how changes in gene expression correlate with the presence of RARγ and AR provides insight into how these proteins influence cell behavior.

3. miRNA Impact Studies

Researchers have also investigated how miR-96 affects the interactions between RARγ and AR. By manipulating miR-96 levels in prostate cancer cells, scientists can see how these changes impact cell growth and response to treatment. This provides important information on potential therapeutic targets.

Findings on RARγ and AR Interaction

Researchers found that RARγ can enhance the ability of AR to bind to DNA and regulate gene expression. In studies with different prostate cancer cell lines, higher levels of RARγ led to more effective AR functions. This suggests that RARγ could help restore normal cell behavior in aggressive prostate cancer.

However, when miR-96 is overexpressed, it can inhibit the function of RARγ, leading to a reduction in its positive effects on AR. This indicates that therapies targeting miR-96 may enhance the activity of RARγ and improve treatment outcomes.

Implications for Treatment Strategies

Understanding the interactions between RARγ, AR, and miR-96 opens the door for new treatment strategies. Researchers are investigating ways to manipulate these proteins to restore normal behavior in prostate cancer cells. Possible approaches include:

  • Targeting miR-96: Reducing miR-96 levels in patients may allow RARγ to perform its normal functions better.
  • Enhancing RARγ Activity: Developing drugs that boost the activity of RARγ may help restore the normal functions of the AR in prostate cancer.
  • Combination Therapies: Using treatments that target both the AR and its associated proteins may improve patient outcomes, especially in cases of treatment resistance.

Conclusion

Prostate cancer remains a significant health challenge, especially in advanced stages. By focusing on the roles of proteins like RARγ and miR-96, researchers hope to develop more effective treatment strategies. Understanding the complex interactions between these proteins and their impact on cell behavior can help pave the way for innovative solutions to improve outcomes for patients facing this disease.

Future Directions

As research continues, scientists aim to deepen their understanding of the biological processes driving prostate cancer. Continued studies will be essential to uncover additional molecular targets and develop new therapeutic strategies to enhance treatment efficacy. The hope is that with better knowledge of the underlying mechanisms, more effective and personalized therapies can be provided to improve quality of life and survival for patients with advanced prostate cancer.

Original Source

Title: Epigenetic disruption of the RARγ complex impairs its function to bookmark AR enhancer interactions required for enzalutamide sensitivity in prostate cancer

Abstract: The current study in prostate cancer (PCa) focused on the genomic mechanisms at the cross-roads of pro-differentiation signals and the emergence of lineage plasticity. We explored an understudied cistromic mechanism involving RAR{gamma}s ability to govern AR cistrome-transcriptome relationships, including those associated with more aggressive PCa features. The RAR{gamma} complex in PCa cell models was enriched for canonical cofactors, as well as proteins involved in RNA processing and bookmarking. Identifying the repertoire of miR-96 bound and regulated gene targets, including those recognition elements marked by m6A, revealed their significant enrichment in the RAR{gamma} complex. RAR{gamma} significantly enhanced the AR cistrome, particularly in active enhancers and super-enhancers, and overlapped with the binding of bookmarking factors. Furthermore, RAR{gamma} expression led to nucleosome-free chromatin enriched with H3K27ac, and significantly enhanced the AR cistrome in G2/M cells. RAR{gamma} functions also antagonized the transcriptional actions of the lineage master regulator ONECUT2. Similarly, gene programs regulated by either miR-96 or antagonized by RAR{gamma} were enriched in alternative lineages and more aggressive PCa phenotypes. Together these findings reveal an under-investigated role for RAR{gamma}, modulated by miR-96, to bookmark enhancer sites during mitosis. These sites are required by the AR to promote transcriptional competence, and emphasize luminal differentiation, while antagonizing ONECUT2.

Authors: Moray J Campbell, S. A. Wani, S. Hussain, J. S. Gray, D. Nayak, H. Tang, L. M. Perez, M. D. Long, M. Siddappa, C. McCabe, M. R. Freeman

Last Update: 2024-02-05 00:00:00

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2023.12.15.571947

Source PDF: https://www.biorxiv.org/content/10.1101/2023.12.15.571947.full.pdf

Licence: https://creativecommons.org/licenses/by/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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