Prostate cancer, notorious for its variable clinical outcomes, poses a significant threat largely due to its capacity for metastasis and therapy resistance. A critical factor enabling this aggressive phenotype is metabolic adaptation, particularly glycolysis, which cancer cells hijack even in oxygen-rich environments—a phenomenon famously known as the Warburg effect. Despite the extensive research into cancer metabolism, the precise molecular crosstalk that sustains this aberrant metabolic state alongside cancer progression remained elusive. The new study meticulously deciphers a hitherto uncharted regulatory circuit involving RNA-binding proteins, circular RNAs, microRNAs, and signaling GTPases.

Central to this feedback loop is ESRP1 (Epithelial Splicing Regulatory Protein 1), a splicing factor that orchestrates alternative RNA processing events pivotal in cancer biology. ESRP1 was found to significantly influence the generation of circPHGDH, a circular RNA derived from the PHGDH gene, which intersects oncogenic signaling and metabolism. Unlike linear RNAs, circular RNAs form covalently closed loops, endowing them with enhanced stability and unique regulatory capabilities, including acting as molecular sponges for microRNAs.

circPHGDH emerges as a crucial molecular scaffold in this network by sequestering miR-149, a microRNA that typically functions as a tumor suppressor by downregulating target oncogenes. The sequestration of miR-149 by circPHGDH diminishes its availability, resulting in the derepression of RAP1B, a Ras-related small GTPase implicated in cell proliferation, migration, and invasion. RAP1B, in turn, amplifies signals that upregulate ESRP1, closing the feedback loop that continuously enhances both malignant behaviors and glycolytic metabolism.

This mechanistic insight was substantiated through a series of intricate experiments employing prostate cancer cell lines and patient-derived samples. Molecular assays demonstrated that upregulation of ESRP1 increases circPHGDH levels, which then captures miR-149, leading to elevated RAP1B expression. Knockdown studies disrupting any component of this axis effectively curtailed glycolysis rates, cell proliferation, and invasive capabilities, underscoring the pathological relevance of this feedback loop.

Moreover, metabolic flux analyses revealed that this feedback loop promotes aerobic glycolysis, providing prostate cancer cells with a rapid supply of ATP and biosynthetic intermediates. This metabolic pivot is essential for supporting the energy-intensive processes of cell motility and growth, facilitating metastasis and resistance to conventional therapies. The study’s findings position the ESRP1/circPHGDH/miR-149/RAP1B axis as a critical metabolic and oncogenic hub within prostate cancer pathophysiology.

The research also delves into the therapeutic potential of disrupting this loop. By selectively targeting circPHGDH or modulating miR-149 levels, there is a promising opportunity to reinstate tumor suppressive pathways and impair the metabolic flexibility of cancer cells. Such strategies could pave the way for combination therapies aimed at crippling cancer metabolism and halting tumor progression.

This discovery is particularly exciting because it highlights the multifaceted roles of non-coding RNAs in cancer biology beyond mere genetic expression. The circular RNA circPHGDH exemplifies how non-coding transcripts can intricately modulate microRNA activity and thereby influence signaling cascades that underpin oncogenesis. This paradigm shift extends the horizon of potential molecular targets that were previously underestimated or overlooked.

Additionally, the role of ESRP1 as a splicing regulator adds another layer of complexity. Its involvement in regulating circular RNA production connects alternative splicing with metabolic reprogramming, revealing how post-transcriptional modifications can drive cancer cell behavior. This nexus between RNA processing and metabolic control represents fertile ground for future research and drug development.

The involvement of RAP1B, a member of the Ras superfamily, in this feedback network reaffirms the significance of small GTPases in cancer metastasis. RAP1B’s established functions in cytoskeletal dynamics and integrin-mediated adhesion make it an attractive target for metastasis intervention. The feedback loop tightly couples RAP1B expression to upstream RNA regulators, suggesting new avenues for disrupting metastatic signaling pathways at multiple regulatory junctions.

Importantly, the clinical relevance of this molecular circuitry was validated in prostate cancer tissues where elevated ESRP1, circPHGDH, and RAP1B correlated with aggressive disease phenotypes and poor prognosis. This translational aspect reinforces the potential for biomarker development based on components of the feedback loop, which might assist clinicians in risk stratification and personalized treatment planning.

Furthermore, the insights into metabolic remodeling mediated by this feedback loop resonate with the evolving landscape of cancer metabolism research. Targeting glycolysis has been an attractive yet challenging therapeutic strategy due to the metabolic plasticity of cancer cells. Understanding the upstream regulators such as this RNA-centric axis opens new doors to finely tune metabolic interventions with greater specificity and efficacy.

In sum, the elucidation of the ESRP1/circPHGDH/miR-149/RAP1B positive feedback loop not only advances our understanding of prostate cancer biology but also offers a compelling framework for therapeutic innovation. By bridging molecular RNA biology, metabolic adaptation, and oncogenic signaling, this study provides a holistic view of tumor progression mechanisms, charting a promising path toward more effective cancer treatments.

As the field moves forward, exploring the broader applicability of such feedback loops across different cancer types and understanding their interactions with other oncogenic networks will be paramount. The integration of high-throughput molecular profiling and functional genomics will undoubtedly accelerate the discovery of similar regulatory circuits, propelling cancer research into an era of precision medicine that targets the cancer cell’s nutri-oncogenic dependencies.

This landmark study published in Experimental & Molecular Medicine encapsulates the potential of combining RNA biology and metabolism to unravel the enigmatic nature of cancer malignancy. By decoding the sophisticated feedback loop at the heart of prostate cancer’s metabolic and proliferative prowess, researchers have illuminated a beacon of hope that might soon be harnessed to thwart this devastating disease.

Subject of Research: Molecular mechanisms underpinning malignant behaviors and metabolic reprogramming in prostate cancer cells.

Article Title: A ESRP1/circPHGDH/miR-149/RAP1B positive feedback loop promotes the malignant behaviors and glycolysis of prostate cancer cell.

Article References:
Wang, X., Yu, L., Qian, X. et al. A ESRP1/circPHGDH/miR-149/RAP1B positive feedback loop promotes the malignant behaviors and glycolysis of prostate cancer cell. Exp Mol Med (2026). https://doi.org/10.1038/s12276-026-01646-x

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01646-x

The challenge in treating CRPC-NE lies in its aggressive nature and diminished dependence on androgen receptor signaling—a pathway conventional therapies target. Tumors frequently circumvent AR blockade by adopting neuroendocrine phenotypes, which no longer respond to AR inhibitors like enzalutamide, leading to poor clinical outcomes. Through sophisticated genetic manipulation of patient-derived organoid models, the research team demonstrated that ablating NSD2 reactivates AR expression and reinstitutes tumor vulnerability to enzalutamide, offering a novel method to overcome therapeutic resistance.

In an extensive series of experiments, NSD2 was inactivated via CRISPR-Cas9 mediated gene knockout in neuroendocrine prostate cancer organoids. Remarkably, this intervention reinstated AR protein levels that had previously been downregulated in CRPC-NE states. Employing dose–response assays, the investigators observed a significant reduction in organoid growth upon treatment with enzalutamide post-NSD2 targeting, with half-maximal inhibitory concentrations (IC50) plummeting below 3 micromolar. This quantitative shift underscored a dramatic re-sensitization of cancer cells to androgen deprivation therapies.

Extending these findings to in vivo models, the team employed subcutaneous grafting of both NSD2-deficient and control organoids into immunodeficient NOD/SCID mice. Upon reaching a critical tumor size, animals were treated with enzalutamide or vehicle control. Tumors lacking NSD2 exhibited significantly impaired growth under androgen blockade, while controls continued to proliferate unabated. Histological examination revealed a profound phenotypic switch; loss of neuroendocrine markers coupled with decreased proliferation indices such as Ki67 and resurgence of adenocarcinoma characteristics highlighted epigenetic reversion towards a more canonical prostate cancer state.

Parallel experiments utilizing human-derived MSKPCa10 organoids substantiated the translational relevance of these findings. NSD2 knockout in these human cells similarly restored responsiveness to enzalutamide both in vitro and in xenograft models, suggesting a conserved mechanism linking NSD2 activity to drug resistance across species. This critical validation establishes NSD2 as a viable target for clinical intervention in therapy-refractory prostate cancers.

Mechanistic insights at the molecular level revealed that NSD2 depletion triggers a global reprogramming of androgen receptor signaling. The expression of classical AR target genes showed robust enrichment post-NSD2 targeting, an effect confirmed at single-cell resolution. Notably, NSD2-deficient organoids manifested a proliferative response to the AR agonist dihydrotestosterone (DHT), which was absent in controls—indicating a restoration of functional AR signaling capable of modulating tumor cell growth.

This study situates NSD2 as a central epigenetic effector that governs phenotypic plasticity in prostate cancer, facilitating the shift from AR-dependent adenocarcinoma to neuroendocrine phenotypes upon which standard therapies fail. By reversing this epigenetic switch, NSD2 inhibition reinstates the canonical AR transcriptional program, reversing resistance and sensitizing tumors to enzalutamide. These findings unlock new paths for targeted epigenetic therapy, potentially combining NSD2 inhibitors with existing AR antagonists to overcome resistance mechanisms.

Furthermore, the work highlights the utility of patient-derived organoids as powerful preclinical platforms enabling precise genetic editing and pharmacological testing. This approach allows real-time evaluation of molecular dependencies within heterogeneous cancer cell populations, accelerating the discovery of context-specific vulnerabilities. The successful translation of organoid-based results into in vivo murine models strengthens the potential for rapid clinical application.

Overall, this paradigm-changing research advances our understanding of molecular determinants underpinning prostate cancer evolution and therapy resistance. It underscores the intricate interplay between epigenetic modifiers and hormonal signaling pathways, offering hope for more durable and effective interventions against metastatic prostate cancer. With further development, NSD2 targeting could usher in a new era of precision epigenetic therapies complementing androgen receptor blockade.

The promising results prompt urgent exploration into the development of selective NSD2 inhibitors suitable for clinical use. Future investigations will be crucial to unravel potential off-target effects, establish optimal dosing regimens, and assess therapeutic windows when combined with enzalutamide. Given the dire prognosis associated with CRPC-NE, this line of research may significantly extend survival and improve quality of life for affected patients.

In light of these discoveries, integrating epigenetic modulation strategies into standard prostate cancer treatment algorithms appears an auspicious direction. The elucidation of resistance reversal mechanisms by NSD2 loss provides a conceptual blueprint for tackling the heterogeneity and adaptability that have so far confounded durable responses in late-stage disease. As research progresses, the prospect of overcoming the deadliest phenotypes of prostate cancer moves closer to reality.

These breakthroughs also raise compelling questions about the broader role of epigenetic regulators in cancer plasticity and drug resistance beyond prostate cancer. By exploiting similar vulnerabilities in other malignancies exhibiting lineage plasticity, targeted NSD2 inhibition or analogous epigenetic reprogramming might enhance responsiveness to a variety of existing therapies. This study therefore opens avenues of translational potential across oncology.

In conclusion, the identification of NSD2 as a pivotal regulator of therapeutic plasticity and resistance in neuroendocrine prostate cancer represents a milestone in cancer epigenetics and precision medicine. The restoration of enzalutamide sensitivity via NSD2 targeting reveals actionable vulnerabilities that can be leveraged to design revolutionary treatment combinations. This paradigm shift affords renewed hope for patients battling drug-resistant prostate cancer and exemplifies the power of integrating genetic and epigenetic insights to surmount clinical challenges.

Subject of Research: Epigenetic regulation and therapeutic resistance in neuroendocrine prostate cancer

Article Title: NSD2 targeting reverses plasticity and drug resistance in prostate cancer

Article References:
Li, J.J., Vasciaveo, A., Karagiannis, D. et al. NSD2 targeting reverses plasticity and drug resistance in prostate cancer. Nature (2025). https://doi.org/10.1038/s41586-025-09727-z

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41586-025-09727-z