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The clock gene BHLHE40 and atypical CCNG2 control androgen-induced cellular senescence as a novel tumor suppressive pathway in prostate cancer

ABSTRACT: The androgen receptor (AR) is a therapeutic target of prostate cancer (PCa). Targeted AR therapy commonly uses androgen deprivation therapy (ADT) and AR antagonists to reduce androgen levels and inhibit tumor growth. Surprisingly, treatment with supraphysiological androgen level (SAL) can also inhibit the growth of PCa. SAL (R1881) was shown to induce cellular senescence in PCa. Knockdown of BHLHE40 in C4-2 and LNCaP cell lines indicates that BHLHE40 mediates SAL-induced cellular senescence as a possible tumor suppressive pathway. The RNA-seq from BHLHE40 knocked down C4-2 cells confirmed that BHLHE40 regulates cellular senescence and associated pathways. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 regulated transcriptome and the SAL-changed transcriptome leading to four classes of up-and downregulated BHLHE40 transcriptome landscapes overlapping with that of AR. Further RNA-seq analyses revealed that the tumor suppressive cyclin G2 (CCNG2) emerged as a novel downstream target of BHLHE40. Knockdown of CCNG2 suggests that it mediates SAL-induced cellular senescence providing evidence of a novel pathway by the AR-BHLHE40-CCNG2 axis to mediate androgen-induced cellular senescence as a novel tumor suppressive pathway in PCa cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262117 | GEO | 2024/06/21

REPOSITORIES: GEO

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Project description:The bipolar androgen therapy (BAT) to treat prostate cancer includes cycles of supraphysiological androgen levels (SAL) under continuous androgen deprivation therapy (ADT). We showed previously that SAL induces cellular senescence in androgen-sensitive PCa cells and ex vivo in PCa tumor samples from patients that underwent radical prostatectomy. Here, we show that SAL induces cellular senescence in both, castration sensitive (CSPC) LNCaP and castration resistant PCa (CRPC) C4-2 cells through the cell cycle inhibitor p15. Treatment with the Akt inhibitor (Akti) potently inhibited SAL-induced expression of p15 and cellular senescence in both cell lines. Proximity ligation assays (PLA) combined with high-resolution laser-scanning microscopy indicate that SAL promotes interaction of endogenous androgen receptor (AR) with endogenous Akt in cytoplasm as well as in nucleus after 72 hours hormone treatment. This suggests that the AR interacts with Akt also in a long-term manner. Transcriptome sequencing (RNA-seq) comparing the SAL-induced transcriptomes of LNCaP with C4-2 cells as well as of Akti treated cells revealed landscapes for cell senescence. Interestingly, one of the identified genes is the lncRNASAT1. SAL treatment of native patient tumor samples ex vivo results in upregulation of lncRNASAT1. The lncRNASAT1 is down-regulated in PCa tumor tissues compared to non-tumor tissues of same patients indicating a tumor suppressive function. Knockdown indicates that the lncRNASAT1 is crucial for SAL-induced cancer cell senescence and regulates LNCaP cell proliferation being an upstream factor for pAkt and for p15. Further, knockdown of lncRNASAT1 inhibits LNCaP cell proliferation by low androgen levels but enhances proliferation by SAL. This suggests that lncRNASAT1 serves as a tumor suppressor with SAL. Interestingly, immunoprecipitation of AR detected lncRNASAT1 as an AR interacting partner that regulates AR target gene expression. Thus, we identified a novel pathway of androgen signaling as the AR- lncRNASAT1- Akt- p15INK4b- axis to mediate SAL-induced cellular senescence.

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The clock gene BHLHE40 and atypical CCNG2 control androgen-induced cellular senescence as a novel tumor suppressive pathway in prostate cancer

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