Outcomes of a recent study by researchers at the Mays Cancer Center at The University of Texas Health Science Center at San Antonio (UT Health San Antonio)demonstrates that altering certain molecular interactions could yield new strategies for treating prostate cancer and related diseases.[1]

The study focused on androgen receptors (AR), protein molecules that help direct the development of male sexual characteristics, essentially by turning genes on or off as necessary. Androgen receptor, which are also known as NR3C4 or nuclear receptor subfamily 3, group C, member 4, is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus. Androgen receptors are most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.[2][3]

Optimum level
The researchers determined that an optimum level of androgen receptor “multivalent interactions” likely is required for proper function. Multivalent interactions involve a simultaneous binding of multiple molecules on the same regulatory chromatin sites to control gene expression. (Chromatin refers to a mixture of DNA and proteins that form the chromosomes found in cells.) The scientists also concluded that alterations of these interactions might underlie the cause and development of disease.

“Our results provide molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR multivalent interactions,” explained Zhijie “Jason” Liu, PhD, associate professor and CPRIT Scholar in Cancer Research with Mays Cancer Center and the Institute of Biotechnology of the Department of Molecular Medicine at UT Health San Antonio.

Liu is lead author of study  published September 21, 2023 issue in Molecular Cell, a journal of research in molecular biology. Other researchers are from the Sam and Ann Barshop Institute for Longevity and Aging Studies at UT Health San Antonio; the California Institute of Technology; and the Duke Cancer Institute at Duke University.

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The researchers observed that androgen receptors form local high-concentration “condensates” – membrane-less subunits that carry out specialized cell functions – through protein-clustering interactions. These are driven by certain multivalent interactions in response to androgen hormone stimulation.

The researchers determined that disturbing those condensates impairs androgen receptor function in the assembly of “enhancers,” referring to DNA sequences that activate transcription independently.

“Our work using AR as an example provides evidence for the importance of maintaining precise levels of multivalent interactions to achieve beneficial hormone-induced enhancer assembly events,” Liu said. “Collectively, our results suggest that disruption of the fine-tuned AR protein multivalent interactions might underlie AR-related human pathologies.

“Androgen receptors multivalent interactions,” lui concluded, “could be pharmacologically targeted to treat prostate cancer and other AR-involved diseases.”

References
[1] Chen L, Zhang Z, Han Q, Maity BK, Rodrigues L, Zboril E, Adhikari R, Ko SH, Li X, Yoshida SR, Xue P, Smith E, Xu K, Wang Q, Huang TH, Chong S, Liu Z. Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions. Mol Cell. 2023 Oct 5;83(19):3438-3456.e12. doi: 10.1016/j.molcel.2023.08.027. Epub 2023 Sep 21. PMID: 37738977.
[2] Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev. 2006 Dec;58(4):782-97. doi: 10.1124/pr.58.4.9. PMID: 17132855.
[3] Roy AK, Lavrovsky Y, Song CS, Chen S, Jung MH, Velu NK, Bi BY, Chatterjee B. Regulation of androgen action. Vitam Horm. 1999;55:309-52. doi: 10.1016/s0083-6729(08)60938-3. PMID: 9949684.

Featured image: hands with blue prostate cancer awareness ribbon. Photo courtesy:© 2016 – 2023. Fotolia/Adobe. Used with permission.

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