A role for androgen receptor variant 7 in sensitivity to therapy: Involvement of IGFBP-2 and FOXA1

Biernacka, Kalina; Barker, Roger A.; Sewell, Andrew; Bahl, Amit; Perks, Claire M

doi:10.1016/j.tranon.2023.101698

Cited by 2 publications

(1 citation statement)

References 50 publications

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“…It has been shown that pre-mRNAs from approximately 95% of human genes with multiple exons undergo AS, resulting in multiple protein isoforms with different structures and functions from a single gene. 6 Several studies have shown that defects in AS regulation may be the initial trigger for various diseases, including cancer, [7][8][9] cardiovascular diseases, 10 neurodegenerative diseases, 11,12 and neuromuscular diseases. 13 Since the completion of the sequencing and annotation of the human genome, several next-generation sequencing techniques have become available.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing in mechanically stretched podocytes as a model of glomerular hypertension

Mattias,

Tsoy,

Hammer

et al. 2024

Preprint

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Alterations in pre-mRNA splicing play an important role in disease pathophysiology. However, the role of alternative splicing (AS) for podocytes in hypertensive nephropathy (HN) has not been investigated. The purpose of the Sys_CARE project was to identify AS events that play a role in the development and progression of HN. For this, murine podocytes were exposed to mechanical stretch, after which proteins and mRNA were analyzed by proteomics, RNA-Seq and several bioinformatic AS tools. Based on transcriptomics and proteomics analysis we could observe significant changes in gene expression and abundance of proteins under mechanical stretch compared to unstretched conditions. By RNA-Seq, we identified over 1000 different splicing events including all types of AS events. We identified 17 genes that showed an AS event in four different splicing analysis tools. We focused on Myl6, a component of the myosin protein complex, and Shroom3, an actin-binding protein crucial for podocyte function. We found two Shroom3 isoforms that showed significant changes in expression upon mechanical stretch, which was verified by qRT-PCR and in situ hybridization. Furthermore, we observed an expression switch of two Myl6 isoforms after mechanical stretch. This switch is accompanied by a change in a C-terminally located amino acid sequence. In summary, mechanical stretch of cultured podocytes is an excellent model to simulate hypertensive nephropathy. In depth RNA-Seq analysis disclosed alternative splicing events, such as in Shroom3 and Myl6, which may play a crucial role in the pathophysiology of hypertension-induced nephropathy.

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Section: Introductionmentioning

confidence: 99%

Alternative splicing in mechanically stretched podocytes as a model of glomerular hypertension

Mattias,

Tsoy,

Hammer

et al. 2024

Preprint

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MED12 and CDK8/19 Modulate Androgen Receptor Activity and Enzalutamide Response in Prostate Cancer

Andolfi,

Bartolini,

Morales

et al. 2024

Endocrinology

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Prostate cancer progression is driven by androgen receptor (AR) activity, which is a target for therapeutic approaches. Enzalutamide is an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One of these mechanisms is the expression of AR-V7, a constitutively active AR splice variant. The Mediator complex is a multisubunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase (CDK)8, or its paralog CDK19, are components of the kinase module that regulates the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and the enzalutamide response. We inhibited MED12 expression and CDK8/19 activity in LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), and PC3 (AR−, enzalutamide-insensitive) cells. Both MED12 and CDK8/19 inhibition reduced cell proliferation in all cell lines, and MED12 inhibition reduced proliferation in the respective 3D spheroids. MED12 knockdown significantly inhibited c-Myc protein expression and signaling pathways. In 22Rv1 cells, it consistently inhibited the AR response, prostate-specific antigen (PSA) secretion, AR target genes, and AR-V7 expression. Combined with enzalutamide, MED12 inhibition additively decreased the AR activity in both LNCaP and 22Rv1 cells. CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer.

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A role for androgen receptor variant 7 in sensitivity to therapy: Involvement of IGFBP-2 and FOXA1

Cited by 2 publications

References 50 publications

Alternative splicing in mechanically stretched podocytes as a model of glomerular hypertension

Alternative splicing in mechanically stretched podocytes as a model of glomerular hypertension

MED12 and CDK8/19 Modulate Androgen Receptor Activity and Enzalutamide Response in Prostate Cancer

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