In an extraordinary leap forward in cancer biology, researchers have unraveled a complex molecular mechanism that fuels the aggressiveness and metabolic rewiring of prostate cancer cells. This groundbreaking study sheds light on how a positive feedback loop involving ESRP1, circPHGDH, miR-149, and RAP1B drives both malignancy and heightened glycolysis—the biochemical process cancer cells exploit to meet their energy demands. The implications of these findings hold promise for developing novel therapeutic strategies targeting prostate cancer, a disease that remains a formidable health challenge worldwide.
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
