GEO series
5β-Dihydrotestosterone and mutant androgen receptor vulnerability in prostate cancer
GSE339459
Homo sapiens
Expression profiling by high throughput sequencing
30 samples
Submitted 2026/08/08
Platform GPL24676
Summary
BACKGROUND Bipolar androgen therapy (BAT) exploits the paradoxical vulnerability of castration-resistant prostate cancer (CRPC) to supraphysiologic androgen, but current BAT uses testosterone (T), which broadly activates wild-type androgen receptor (AR) in normal androgen-responsive tissues and can cause systemic androgenic effects. 5β-Dihydrotestosterone (5β-DHT), a naturally occurring T metabolite, has been considered androgenically inactive because of weak wild-type AR activity. Here, we examined whether 5β-DHT and related 5β-reduced metabolites activate mutant AR signaling and reproduce BAT-like growth suppression. METHODS Six 5β-reduced T metabolites were evaluated in C4-2 and LNCaP prostate cancer cells under androgen-depleted and BAT-like conditions. AR dependence and mutant-specific activity were assessed using enzalutamide, AR-null PC-3 cells, and PC-3 cells expressing AR-W742C or AR-H875Y. Cell proliferation, AR-responsive reporter activity, RT-qPCR, RNA sequencing with gene set enrichment analysis, immunoblotting, and senescence-associated β-galactosidase staining were used to characterize ligand responses. RESULTS At nanomolar concentrations, 5β-DHT and 3β-etiocholanediol (3β-ecdiol) induced AR target genes and promoted AR-dependent C4-2 and LNCaP growth, although less potently than T. RNA sequencing showed that both metabolites activated the T-regulated AR transcriptional program with smaller differentially expressed gene footprints. At high concentrations, 5β-DHT, but not the weaker agonist 3β-ecdiol or progesterone-class steroids, suppressed C4-2 and LNCaP proliferation. High-dose 5β-DHT also activated AR and suppressed growth in PC-3 cells expressing AR-W742C or AR-H875Y, whereas AR-null PC-3 cells were unaffected. High-dose 5β-DHT enriched androgen-response and senescence programs, suppressed G2M, E2F, and MYC-associated pathways, increased p21, p27, and p57, reduced RB phosphorylation and SKP2, and induced senescence-associated β-galactosidase activity.
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE339459_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 30 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1498880 and SRA study SRP720242. Searching any of these in the dataset finder brings you back here.
Study design
10 conditions, mostly in triplicate
C4-2, vehicle (ethanol), csFBS, 24 h, biol ×3
C4-2, testosterone 10 nM, csFBS, 24 h, biol ×3
C4-2, 5beta-DHT 10 nM, csFBS, 24 h, biol ×3
C4-2, 3beta-ecdiol 10 nM, csFBS, 24 h, biol ×3
C4-2, vehicle (ethanol), 10% FBS, Day 1 (24 h… ×3
C4-2, testosterone 100 nM, 10% FBS, Day 1 (24… ×3
C4-2, 5beta-DHT 100 nM, 10% FBS, Day 1 (24 h)… ×3
C4-2, vehicle (ethanol), 10% FBS, Day 3 (72 h… ×3
+2 more
Supports a between-group comparison across 30 samples.
10 replicated groups read from 30 sample titles; they account for 30 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM9895980 C4-2, vehicle (ethanol), csFBS, 24 h, biol. rep. 1
- GSM9895981 C4-2, vehicle (ethanol), csFBS, 24 h, biol. rep. 2
- GSM9895982 C4-2, vehicle (ethanol), csFBS, 24 h, biol. rep. 3
- GSM9895983 C4-2, testosterone 10 nM, csFBS, 24 h, biol. rep. 1
- GSM9895984 C4-2, testosterone 10 nM, csFBS, 24 h, biol. rep. 2
- GSM9895985 C4-2, testosterone 10 nM, csFBS, 24 h, biol. rep. 3
- GSM9895986 C4-2, 5beta-DHT 10 nM, csFBS, 24 h, biol. rep. 1
- GSM9895987 C4-2, 5beta-DHT 10 nM, csFBS, 24 h, biol. rep. 2
- GSM9895988 C4-2, 5beta-DHT 10 nM, csFBS, 24 h, biol. rep. 3
- GSM9895989 C4-2, 3beta-ecdiol 10 nM, csFBS, 24 h, biol. rep. 1
- GSM9895990 C4-2, 3beta-ecdiol 10 nM, csFBS, 24 h, biol. rep. 2
- GSM9895991 C4-2, 3beta-ecdiol 10 nM, csFBS, 24 h, biol. rep. 3
- GSM9895992 C4-2, vehicle (ethanol), 10% FBS, Day 1 (24 h), biol. rep. 1
- GSM9895993 C4-2, vehicle (ethanol), 10% FBS, Day 1 (24 h), biol. rep. 2
- GSM9895994 C4-2, vehicle (ethanol), 10% FBS, Day 1 (24 h), biol. rep. 3
- GSM9895995 C4-2, testosterone 100 nM, 10% FBS, Day 1 (24 h), biol. rep. 1
- GSM9895996 C4-2, testosterone 100 nM, 10% FBS, Day 1 (24 h), biol. rep. 2
- GSM9895997 C4-2, testosterone 100 nM, 10% FBS, Day 1 (24 h), biol. rep. 3
- GSM9895998 C4-2, 5beta-DHT 100 nM, 10% FBS, Day 1 (24 h), biol. rep. 1
- GSM9895999 C4-2, 5beta-DHT 100 nM, 10% FBS, Day 1 (24 h), biol. rep. 2
- GSM9896000 C4-2, 5beta-DHT 100 nM, 10% FBS, Day 1 (24 h), biol. rep. 3
- GSM9896001 C4-2, vehicle (ethanol), 10% FBS, Day 3 (72 h), biol. rep. 1
- GSM9896002 C4-2, vehicle (ethanol), 10% FBS, Day 3 (72 h), biol. rep. 2
- GSM9896003 C4-2, vehicle (ethanol), 10% FBS, Day 3 (72 h), biol. rep. 3
- GSM9896004 C4-2, testosterone 100 nM, 10% FBS, Day 3 (72 h), biol. rep. 1
- GSM9896005 C4-2, testosterone 100 nM, 10% FBS, Day 3 (72 h), biol. rep. 2
- GSM9896006 C4-2, testosterone 100 nM, 10% FBS, Day 3 (72 h), biol. rep. 3
- GSM9896007 C4-2, 5beta-DHT 100 nM, 10% FBS, Day 3 (72 h), biol. rep. 1
- GSM9896008 C4-2, 5beta-DHT 100 nM, 10% FBS, Day 3 (72 h), biol. rep. 2
- GSM9896009 C4-2, 5beta-DHT 100 nM, 10% FBS, Day 3 (72 h), biol. rep. 3
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