Androgen deprivation‑induced OPHN1 amplification promotes castration‑resistant prostate cancer

Liu, Junjiang; Zhang, Yunxia; Li, Shoubin; Sun, Fa; Wang, Gang; Dong, Wei; Yang, Tao; Gu, Shouyi

doi:10.3892/or.2021.8214

Cited by 6 publications

(3 citation statements)

References 50 publications

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“…Since the 5hmC capture assay is highly specific, the high level of 5hmC at AR but not nearby gene loci indicate specific activation of AR expression. Additionally, the AR is commonly co-amplified with nearby genes [42,43], the lack of co-amplification also supports the notion that the activation of androgen response gene sets may not be caused by AR amplification in this study cohort.…”

Section: Baseline Gene Set Activity Score Predicts Treatment Resistan...supporting

confidence: 82%

5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies

Li,

Huang,

Huang

et al. 2023

Preprint

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Background: Currently there are no biomarkers to identify resistance to androgen-deprivation therapy (ADT) in men with hormone-naive prostate cancer. 5-hydroxymethylcytosines (5hmC) in the gene body are associated with gene activation and are critical for epigenomic regulation of cancer progression. Objective: To evaluate whether 5hmC signature in cell-free DNA (cfDNA) predicts early ADT resistance. Design, Setting, and Participants: Serial plasma samples from 55 prostate cancer patients receiving ADT were collected at three timepoints including baseline (prior to initiating ADT, N=55), 3-month (after initiating ADT, N=55), and disease progression (N=15) within 24 months or 24-month if no progression was detected (N=14). 20 of the 55 patients showed disease progression during the 24-month follow-up. The remaining 35 patients showed no progression in the same follow-up period. Outcome Measurements and Statistical Analysis: cfDNA (5-10ng) was used for selective chemical labeling (hMe-Seal) sequencing to map 5hmC abundance across the genome. Read counts in gene bodies were normalized with DESeq2. Differential methylation and gene set enrichment analyses were performed to identify the 5hmC-enriched genes and biological processes that were associated with disease progression. Kaplan-Meir analysis was utilized to determine the association of 5hmC signatures with progression-free survival. Results and Limitations: 5hmC-sequencing generated an average of 18.6 (range 6.03 to 42.43) million reads per sample with 98% (95-99%) mappable rate. Baseline sample comparisons identified significant 5hmC difference in 1,642 of 23,433 genes between 20 patients with progression and 35 patients without progression (false discovery rate, FDR<0.1). Patients with progression showed significant enrichments in multiple hallmark gene sets with androgen responses as the top enriched gene set (FDR=1.19E-13). Interestingly, this enrichment was driven by a subgroup of patients with disease progression featuring a significant 5hmC hypermethylation of the gene sets involving AR, FOXA1 and GRHL2. To quantify overall activities of these gene sets, we developed a gene set activity score algorithm using a mean value of log2 ratios of gene read counts in an entire gene set. We found that the activity scores in these gene sets were significantly higher in this subgroup of patients with progression than in the remaining patients regardless of the progression status. Furthermore, the high activity scores in these gene sets were associated with poor progression-free survival (p <0.05). Longitudinal analysis showed that activity scores in this subgroup with progression were significantly reduced after 3-month ADT but returned to high levels when the disease was progressed. Conclusions: 5hmC-sequencing in cfDNA identified a subgroup of prostate cancer patients with preexisting activation (5hmC hypermethylation) of gene sets involving AR, FOXA1 and GRHL2 before initiating ADT. Activity scores in these gene sets may serve as sensitive biomarkers to determine treatment resistance, monitor disease progression and potentially identify patients who would benefit from upfront treatment intensification. More studies are needed to validate this initial finding.

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Section: Baseline Gene Set Activity Score Predicts Treatment Resistan...supporting

confidence: 82%

5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies

Li,

Huang,

Huang

et al. 2023

Preprint

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“…Further, we noticed that chromosome X loss was most obvious in BUB1‐KD cells, and OPHN1, DOCK11 and CENPI were the most apparently changed genes in chromosome X (data not shown). OPHN1 overexpression was observed in prostate cancer (PCa) after androgen deprivation therapy, which promoted PCa progression and cell survival 62 . Moreover, CENPI is related to adverse outcomes and promotes CIN in ER ‐positive breast cancer 63 .…”

Section: Discussionmentioning

confidence: 99%

“…OPHN1 overexpression was observed in prostate cancer (PCa) after androgen deprivation therapy, which promoted PCa progression and cell survival. 62 Moreover, CENPI is related to adverse outcomes and promotes CIN in ER ‐positive breast cancer. 63 Given the cancer‐promoting effect of these genes, how BUB1 affects the changes of these chromosomes need further study.…”

Section: Discussionmentioning

confidence: 99%

BUB1/KIF14 complex promotes anaplastic thyroid carcinoma progression by inducing chromosome instability

Jin,

Ding,

Chen

et al. 2024

J Cellular Molecular Medi

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Chromosome instability (CIN) is a common contributor driving the formation and progression of anaplastic thyroid cancer (ATC), but its mechanism remains unclear. The BUB1 mitotic checkpoint serine/threonine kinase (BUB1) is responsible for the alignment of mitotic chromosomes, which has not been thoroughly studied in ATC. Our research demonstrated that BUB1 was remarkably upregulated and closely related to worse progression‐free survival. Knockdown of BUB1 attenuated cell viability, invasion, migration and induced cell cycle arrests, whereas overexpression of BUB1 promoted the cell cycle progression of papillary thyroid cancer cells. BUB1 knockdown remarkably repressed tumour growth and tumour formation of nude mice with ATC xenografts and suppressed tumour metastasis in a zebrafish xenograft model. Inhibition of BUB1 by its inhibitor BAY‐1816032 also exhibited considerable anti‐tumour activity. Further studies showed that enforced expression of BUB1 evoked CIN in ATC cells. BUB1 induced CIN through phosphorylation of KIF14 at serine1292 (Ser1292). Overexpression of the KIF14ΔSer1292 mutant was unable to facilitate the aggressiveness of ATC cells when compared with that of the wild type. Collectively, these findings demonstrate that the BUB1/KIF14 complex drives the aggressiveness of ATC by inducing CIN.

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Bavdegalutamide (ARV-110): a potent PROTAC androgen receptor degrader for the treatment of metastatic-castration resistant prostate cancer

Ma,

Han

2025

Drug Discovery Stories

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Androgen deprivation‑induced OPHN1 amplification promotes castration‑resistant prostate cancer

Cited by 6 publications

References 50 publications

5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies

5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies

BUB1/KIF14 complex promotes anaplastic thyroid carcinoma progression by inducing chromosome instability

Bavdegalutamide (ARV-110): a potent PROTAC androgen receptor degrader for the treatment of metastatic-castration resistant prostate cancer

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