Biology subjects

Paakinaho, V.

Publications and source records attributed to Paakinaho, V..

5 recordsLinked to original sources

bioRxiv2025

p63-GATA2 molecular switch mediates the tumor suppressor to oncogene transition of glucocorticoid receptor in the prostate

Glucocorticoids are widely used to alleviate inflammation and treatment-related side effects in prostate cancer (PCa), particularly to counteract abiraterone-induced cortisol suppression. However, the glucocorticoid receptor (GR) exhibits a dual role exerting tumor-suppressive effects by inhibiting early-stage PCa cell proliferation, while also promoting oncogenic progression by mediating antiandrogen resistance. The molecular mechanisms underlying this functional dichotomy have remained elusive and poorly characterized. Using genome-wide analyses and CRISPR-based genome editing, we identified the tumor protein p63 as a key mediator of GRs tumor-suppressive chromatin activity and maintenance of basal epithelial cell identity. Loss of p63 reprograms GR activity toward an oncogenic state, marked by basal-to-luminal transition, enhanced cell migration, invasion, and altered morphology accompanied by increased epithelial-mesenchymal transition markers. This functional shift is driven by elevated expression of transcription factors GATA2 and FRA1, which remodel GRs chromatin binding and transcriptional output to activate oncogenic signaling pathways. Together, our findings uncover a molecular switch that governs the dual role of GR in PCa, establishing transcription factor crosstalk as a critical regulator of GR-driven oncogenic reprogramming and cellular plasticity. These findings establish a framework for understanding glucocorticoid-induced tumor suppression and highlight GATA2 and FRA1 as potential targets to mitigate GR-mediated resistance in PCa.

genomics↗

bioRxiv2024

Steroid receptor-assisted loading modulates transcriptional responses in prostate cancer cells

Steroid receptors are involved in a wide array of crosstalk mechanisms that regulate diverse biological processes, with significant implications in diseases, particularly in cancers. In prostate cancer, indirect crosstalk between androgen receptor (AR) and glucocorticoid receptor (GR) is well-documented, wherein AR suppression by antiandrogen therapy leads to elevated GR levels, enabling GR to compensate for and replace AR signaling. However, the existence and impact of direct chromatin crosstalk between AR and GR in prostate cancer have remained elusive. Our genome-wide investigations reveal that AR activation significantly expands GR chromatin binding. Mechanistically, AR induces remodeling of closed chromatin sites, facilitating GR binding to inaccessible sites. Importantly, coactivation of AR and GR results in distinct transcriptional responses at both the cell population and single-cell levels. Intriguingly, pathways affected by these transcriptional changes are generally associated with improved patient survival. Thus, the direct crosstalk between AR and GR yields markedly different outcomes from the known role of GR in circumventing AR blockade by antiandrogens.

genomics↗

bioRxiv2023

Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer

Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the antiandrogen therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR function. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs have remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in enzalutamide-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. Moreover, the small-molecule inhibition of coactivator p300s enzymatic activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated antiandrogen resistance.

molecular biology↗

bioRxiv2022

Single-molecule tracking reveals two low-mobility states for chromatin and transcriptional regulators within the nucleus

How transcription factors (TFs) navigate the complex nuclear environment to assemble the transcriptional machinery at specific genomic loci remains elusive. Using single-molecule tracking, coupled with machine learning, we examined the mobility of multiple transcriptional regulators. We show that H2B and ten different transcriptional regulators display two distinct low-mobility states. Our results indicate that both states represent dynamic interactions with chromatin. Ligand activation results in a dramatic increase in the proportion of steroid receptors in the lowest mobility state. Mutational analysis revealed that only chromatin interactions in the lowest mobility state require an intact DNA-binding domain as well as oligomerization domains. Importantly, these states are not spatially separated as previously believed but in fact, individual H2B and TF molecules can dynamically switch between them. Together, our results identify two unique and distinct low-mobility states of transcriptional regulators that appear to represent common pathways for transcription activation in mammalian cells.

biophysics↗

bioRxiv2019

A New Model for Single-Molecule Tracking Analysis of Transcription Factor Dynamics

Single-molecule tracking (SMT) allows the study of transcription factor (TF) dynamics in the nucleus, giving important information regarding the search and binding behaviour of these proteins in the nuclear environment. Dwell time distributions for most TFs have been described by SMT to follow bi-exponential behaviour. This is consistent with the existence of two discrete populations bound to chromatin in vivo, one non-specifically bound to chromatin (i.e. searching mode) and another specifically bound to target sites, as originally defined by decades of biochemical studies. However, alternative models have started to emerge, from multiple exponential components to power-law distributions. Here, we present an analytical pipeline with an unbiased model selection approach based on different statistical metrics to determine the model that best explains SMT data. We found that a broad spectrum of TFs (including glucocorticoid receptor, oestrogen receptor, FOXA1, CTCF) follow a power-law distribution, blurring the temporal line between non-specific and specific binding, and suggesting that productive binding may involve longer binding events than previously thought. We propose a continuum of affinities model to explain the experimental data, consistent with the movement of TFs through complex interactions with multiple nuclear domains as well as binding and searching on the chromatin template.

biophysics↗