Functional circuits of LYL1 controlled by supraphysiological androgen in prostate cancer cells to regulate cell senescence

Sep 21, 2026

Study identifies a molecular mechanism linking supraphysiological androgen (SAL) to cellular senescence in prostate cancer. The androgen receptor (AR) regulates normal prostate biology and cancer proliferation, while SAL treatment is known to inhibit growth and trigger a tumor-suppressive program. Transcriptome and ChIP-seq analyses show LYL1 is induced by the clock gene BHLHE40 and mediates SAL-driven senescence, involving p27kip1 and AR/BHLHE40 recruitment, supported by feedback-loop mapping.

LanguageEnglish

CategoryResearch & Report

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Pages20

Reading Time50 min

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Abstract

Background

Methods

Results

Conclusions

Heidari Horestani et al. Cell Communication and Signaling (2024) 22:590 [https://doi.org/10.1186/s12964-024-01970-7](https://doi.org/10.1186/s12964-024-01970-7) Cell Communication and Signaling RESEARCH Open Access Functional circuits of LYL1 controlled by supraphysiological androgen in prostate cancer cells to regulate cell senescence Mehdi Heidari Horestani 1, Katrin Schindler 1 and Aria Baniahmad 1* Abstract Background Prostate cancer (PCa) is a public health problem mostly reported in developed countries. The androgen receptor (AR) regulates the development and physiological function of normal prostate as well as the proliferation of cancerous prostate tissue. Treatment with supraphysiological androgen levels (SAL) is used in bipolar androgen therapy and inhibits PCa growth, suggesting SAL induces a tumor suppressive program. It was shown that SAL induces cellular senescence, in PCa cell lines, human tumor samples and in xenografted mouse tumor model. Methods Transcriptome and ChIP-seq analysis, PCa spheroids, knockdown (KD), co-immunoprecipitation, qRT-PCR, immune detection, in situ histochemistry. Results Here we show that LYL1 is upregulated by the clock gene BHLHE40 in both C4-2 and LNCaP cells and mediates SAL-induced cellular senescence. LYL1 is a transcriptional co-factor with oncogenic activity in leukemia. However, analysis of a large cohort of PCa patients shows that LYL1 expression is reduced during PCa development and reduced expression is significantly associated with reduced overall survival. SAL induces the expression of LYL1 through upregulation of BHLHE40 . On the other hand, the KD of LYL1 enhances BHLHE40 expression via a negative feedback loop including p27kip1 . Regulatory feedback loops were identified by rescue experiments. Functional analysis revealed that KD of BHLHE40 reduces whereas LYL1 KD enhances p27kip1 levels. The KD of p27kip1 suggests that this cell cycle inhibitor is a mediator of cellular senescence by the BHLHE40-LYL1 regulatory loop. Interestingly, ChIP-seq data revealed recruitment of both AR and BHLHE40 to the LYL1 gene indicating that LYL1 is a novel direct target of both factors. Furthermore, RNA-seq data from C4-2 cells suggests that LYL1 and BHLHE40 encompass a large overlap of genes by SAL suggesting a co-regulatory activity controlled by androgens. In line with this, co-immunoprecipitation suggests LYL1 is in a complex with BHLHE40 and the AR. Conclusions Three novel feed-back loops and a novel AR-BHLHE40 / LYL1-p27kip1 axis has been identified mediating cellular senescence in PCa cells. Keywords Androgen receptor, Androgen-induced cellular senescence, Prostate cancer, LYL1 *Correspondence: Aria Baniahmad [aria.baniahmad@med.uni-jena.de](aria.baniahmad@med.uni-jena.de) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/.)[.](http://creativecommons.org/licenses/by/4.0/.) Heidari Horestani etal. Cell Communication and Signaling (2024) 22:590 Page 2 of 20 Graphical Abstract Background PCa is a public health problem mostly

FAQs

How does supraphysiological androgen affect cellular senescence in prostate cancer cells?

Supraphysiological androgen (SAL) induces a tumor-suppressive program and cellular senescence in prostate cancer cell models. The study shows SAL mediates this process through upregulation of LYL1.

What role does LYL1 play in the LYL1-BHLHE40 regulatory network?

LYL1 is upregulated by BHLHE40 and mediates SAL-induced cellular senescence. Knockdown experiments indicate that LYL1 depletion enhances BHLHE40 expression via feedback circuitry involving p27kip1.

Which molecular targets are directly linked to LYL1 regulation by AR and BHLHE40?

ChIP-seq data show recruitment of AR and BHLHE40 to the LYL1 gene. RNA-seq and co-immunoprecipitation further support co-regulatory activity and a complex containing LYL1, BHLHE40, and AR.

Sep 21, 2026

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