Epigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer

Chakraborty, Goutam; Gupta, Kasmira; Kyprianou, Natasha

doi:10.1038/s41467-023-36253-1

Cited by 13 publications

(5 citation statements)

References 63 publications

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“…Reports indicate that during NE-like transformation, adenocarcinoma cells undergo a series of chromatin modification and epigenetic alterations to enhance neuroendocrine-related gene expression ( 25 , 26 ). To understand whether our derived cell lines follows such characteristic changes in their DNA, we have carried out ATAC-Seq as well as histone ChIP-seq.…”

Section: Resultsmentioning

confidence: 99%

Understanding the role of Pax5 in development of taxane-resistant neuroendocrine like prostate cancers

Dutta,

Bhattacharya,

Harris

et al. 2023

Preprint

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Resistance to the current Androgen Receptor Signaling Inhibitor (ARSI) therapies has led to higher incidences of therapy-induced neuroendocrine-like prostate cancer (t-NEPC). This highly aggressive subtype with predominant small cell-like characteristics is resistant to taxane chemotherapies and has a dismal overall survival. t-NEPCs are mostly treated with platinum-based drugs with a combination of etoposide or taxane and have less selectivity and high systemic toxicity, which often limit their clinical potential. During t-NEPC transformation, adenocarcinomas lose their luminal features and adopt neuro-basal characteristics. Whether the adaptive neuronal characteristics of t-NEPC are responsible for such taxane resistance remains unknown. Pathway analysis from patient gene-expression databases indicates that t-NEPC upregulates various neuronal pathways associated with enhanced cellular networks. To identify transcription factor(s) (TF) that could be important for promoting the gene expression for neuronal characters in t-NEPC, we performed ATAC-Seq, acetylated-histone ChIP-seq, and RNA-seq in our NE-like cell line models and analyzed the promoters of transcriptionally active and significantly enriched neuroendocrine-like (NE-like) cancer-specific genes. Our results indicate that Pax5 could be an important transcription factor for neuronal gene expression and specific to t-NEPC. Pathway analysis revealed that Pax5 expression is involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Further results suggest that depletion of Pax5 disrupts cellular interaction in NE-like cells and reduces surface growth factor receptor activation, thereby, sensitizing them to taxane therapies. Moreover, t-NEPC specific hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression. Based on our study, we concluded that continuous exposure to ARSI therapies leads to epigenetic modifications and Pax5 activation in t-NEPC, which promotes the expression of genes necessary to adopt taxane-resistant NE-like cancer. Thus, targeting the Pax5 axis can be beneficial for reverting their taxane sensitivity.

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Section: Resultsmentioning

confidence: 99%

Understanding the role of Pax5 in development of taxane-resistant neuroendocrine like prostate cancers

Dutta,

Bhattacharya,

Harris

et al. 2023

Preprint

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show abstract

“…Consequently, many patients commence treatment at advanced stages, encountering postoperative biochemical recurrence (BCR) that necessitates conventional chemotherapy and radiotherapy. [5][6][7][8] However, systemic toxicity and tumor resistance to standard treatments can worsen patient prognosis. Specifically, patients with metastatic castrationresistant prostate cancer (mCRPC) frequently develop resistance to taxanes within 8 months, with a poor response rate of approximately 50%.…”

Section: Introductionmentioning

confidence: 99%

“…Tumors of these three types exhibit substantial heterogeneity and propensity for metastasis. Consequently, many patients commence treatment at advanced stages, encountering postoperative biochemical recurrence (BCR) that necessitates conventional chemotherapy and radiotherapy 5–8 . However, systemic toxicity and tumor resistance to standard treatments can worsen patient prognosis.…”

Section: Introductionmentioning

confidence: 99%

Cuproptosis: Mechanism, role, and advances in urological malignancies

Wu,

He,

Liu

et al. 2024

Medicinal Research Reviews

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Prostate, bladder, and kidney cancers are the most common malignancies of the urinary system. Chemotherapeutic drugs are generally used as adjuvant treatment in the middle, late, or recurrence stages after surgery for urologic cancers. However, traditional chemotherapy is plagued by problems such as poor efficacy, severe side effects, and complications. Copper‐containing nanomedicines are promising novel cancer treatment modalities that can potentially overcome these disadvantages. Copper homeostasis and cuproptosis play crucial roles in the development, adaptability, and therapeutic sensitivity of urological malignancies. Cuproptosis refers to the direct binding of copper ions to lipoylated components of the tricarboxylic acid cycle, leading to protein oligomerization, loss of iron–sulfur proteins, proteotoxic stress, and cell death. This review focuses on copper homeostasis and cuproptosis as well as recent findings on copper and cuproptosis in urological malignancies. Furthermore, we highlight the potential therapeutic applications of copper‐ and cuproptosis‐targeted therapies to better understand cuproptosis‐based drugs for the treatment of urological tumors in the future.

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“…Prostate cancer patients are currently treated with active surveillance, radical prostatectomy, external beam radiation therapy, and endocrine therapy to suppress androgens [ 4 , 5 , 6 ]. In particular, androgen deprivation therapy is used for metastatic PC, but patients acquire resistance to androgen deprivation therapy in most cases and eventually develop castration-resistant prostate cancer (CRPC), which has a poor prognosis [ 7 , 8 ]. Localized PC has a 5-year survival rate of almost 100%, while metastatic PC, which has mainly metastasized to bones and other organs, has a 5-year survival rate of less than 30% [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

An Antibody of the Secreted Isoform of Disintegrin and Metalloprotease 9 (sADAM9) Inhibits Epithelial–Mesenchymal Transition and Migration of Prostate Cancer Cell Lines

Jotatsu,

Sung,

et al. 2024

IJMS

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Prostate cancer (PC) is the most common cancer diagnosed in men worldwide. Currently, castration-resistant prostate cancer (CRPC), which is resistant to androgen deprivation therapy, has a poor prognosis and is a therapeutic problem. We investigated the antitumor effects on PC of an antibody neutralizing secreted disintegrin and metalloproteinase domain-containing protein 9 (sADAM9), which is a blood-soluble form. We performed proliferation assays, wound healing assays, invasion assays, Western blot (WB), and an in vivo study in which a sADAM9 neutralizing antibody was administered intratumorally to PC-bearing mice. In invasion assays, the sADAM9 neutralizing antibody significantly inhibited invasion in all cell lines (TRAMP-C2: p = 0.00776, LNCaP: p = 0.000914, PC-3: p = 0.0327, and DU145: p = 0.0254). We examined epithelial–mesenchymal transition (EMT) markers, one of the metastatic mechanisms, in WB and showed downregulation of Slug in TRAMP-C2, LNCaP, and DU145 and upregulation of E-cadherin in TRAMP-C2 and PC-3 by sADAM9 neutralization. In mouse experiments, the sADAM9 neutralizing antibody significantly suppressed tumor growth compared to controls (1.68-fold in TRAMP-C2, 1.89-fold in LNCaP, and 2.67-fold in PC-3). These results suggested that the sADAM9 neutralizing antibody inhibits invasion, migration, and tumor growth in PC. Previous studies examined the anti-tumor effect of knockdown of total ADAM9 or sADAM9, but this study used the new technology of neutralizing antibodies for sADAM9. This may be novel because there was no animal study using a neutralizing antibody for sADAM9 to see the relationship between ADAM9 expression and prostate cancer.

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Epigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer

Cited by 13 publications

References 63 publications

Understanding the role of Pax5 in development of taxane-resistant neuroendocrine like prostate cancers

Understanding the role of Pax5 in development of taxane-resistant neuroendocrine like prostate cancers

Cuproptosis: Mechanism, role, and advances in urological malignancies

An Antibody of the Secreted Isoform of Disintegrin and Metalloprotease 9 (sADAM9) Inhibits Epithelial–Mesenchymal Transition and Migration of Prostate Cancer Cell Lines

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