The research, led by Zihao Deng, Lifang He, and colleagues under corresponding author Yukun Cui at the Cancer Hospital of Shantou University Medical College, tackles a phenomenon known as lineage plasticity. This is the capacity of cancer cells to shed their original identity and adopt alternative cell states when pressured by therapy, a behavior increasingly recognized as a major driver of treatment resistance in prostate cancer and other tumors. In the androgen receptor-low or androgen receptor-null state, prostate cancer cells build extensive epigenetic barriers: their chromatin, the packaged form of DNA inside the nucleus, becomes inaccessible, and the three-dimensional architecture of the genome locks into a repressive topology that keeps the androgen receptor gene and its regulatory elements silenced. How that locking-in happens, and whether it can be reversed, has remained poorly understood.

KIF11, also known as kinesin family member 11, is best known as a mitotic kinesin, a motor protein that drives spindle assembly during cell division and has long been pursued as a chemotherapy target. Existing KIF11 inhibitors tend to work at cytotoxic doses that halt division in any rapidly proliferating cell. The Shantou team took a different angle. Combining public transcriptomic and epigenomic datasets with their own RNA sequencing, ATAC-seq chromatin accessibility profiling, RNA interference, low-dose pharmacological inhibition with the KIF11 inhibitor ispinesib, chromatin immunoprecipitation, chromosome conformation capture, DNA methylation assays, and reporter and therapeutic-response experiments, they asked what happens to prostate cancer cells when KIF11 activity is reduced gently rather than destroyed completely.

The answer surprised them. In androgen receptor-low and androgen receptor-null prostate cancer models, including PC3 and DU145 cells, either RNAi-mediated depletion or low-dose pharmacological inhibition of KIF11 activated androgen receptor-associated transcriptional programs. The cells began, in effect, to remember who they were supposed to be. Chromatin accessibility increased at androgen receptor regulatory regions, and the team measured higher occupancy of FOXA1 and GRHL2, two pioneering transcription factors that act as gatekeepers of the androgen receptor enhancer, at that key regulatory element. At the same time, the co-activator EP300 and the transcription elongation factor SUPT5H showed increased occupancy at androgen receptor regulatory elements, signaling that the locus was not merely open but actively engaged in productive transcription.

The mechanism went deeper than transcription factor recruitment. Using chromosome conformation capture techniques, the researchers showed that KIF11 inhibition reduced DNA methylation at CTCF motifs, the DNA sequences recognized by the CCCTC-binding factor, an architectural protein that anchors loops in the genome. With methylation lifted, CTCF occupancy rose, and the physical communication between enhancers and the androgen receptor promoter strengthened. In other words, KIF11 inhibition did not simply sprinkle activating marks on the genome; it rebuilt the three-dimensional wiring of the androgen receptor locus, constructing enhancer-promoter loops that bring distant regulatory elements into direct contact with the gene they control.

That topological resetting proved remarkably stable. Once the enhancer-promoter architecture was established, it locked in a sustained androgen receptor transcriptional program and created a feed-forward reinforcement circuit in which the reactivated pathway maintained its own expression. Functionally, this drove what the authors describe as a lineage return: androgen-insensitive, androgen receptor-low or null prostate cancer cells transitioned back into an androgen receptor-responsive transcriptional state. The change was not cosmetic. With the androgen receptor machinery restored, the cells regained the very dependency that antiandrogen drugs exploit.

The therapeutic consequences were tested across multiple model systems. In cell-line experiments, patient-derived castration-resistant prostate cancer organoids, and xenograft models in mice, low-dose KIF11 inhibition combined with enzalutamide or apalutamide produced robust growth suppression in tumors that would normally ignore these drugs. Crucially, the KIF11 inhibition used in these experiments was deliberately kept at low, non-cytotoxic doses, avoiding the broad toxicity that would come with hitting every dividing cell. The strategy is therefore conceptually distinct from conventional chemotherapy: rather than killing cancer cells directly, the treatment reprograms their regulatory architecture so that a second, well-tolerated class of drugs can work again.

The findings carry significant implications for how lineage plasticity-driven resistance might be overcome in the clinic. If a subset of patients with androgen receptor-low or null disease could be identified, perhaps through biopsy-based profiling of KIF11 levels, CTCF methylation status, or androgen receptor locus topology, they might become candidates for a re-sensitization strategy in which short-term KIF11 inhibition converts their tumors into androgen receptor-dependent ones before initiating or resuming antiandrogen therapy. The authors note that Y. Cui and Z. Deng have filed a patent application related to the findings, suggesting momentum toward translational development. At the same time, the work remains at the preclinical stage, and questions about dosing windows, patient selection, and safety in humans will need to be addressed in future studies.

Scientifically, the study adds an important dimension to a growing body of work showing that cancer is as much a disease of genome architecture as of genome sequence. The idea that inhibiting a mitotic motor protein could demethylate CTCF sites, reopen chromatin, reorganize enhancer-promoter loops, and ultimately restore a whole lineage identity illustrates how deeply intertwined cell division machinery, epigenetics, and three-dimensional genome organization really are. For patients with castration-resistant prostate cancer whose tumors have gone androgen-receptor silent, the research offers a conceptually elegant possibility: the door that cancer slammed shut can, with the right molecular key, be opened again, and the treatments already on the shelf may once more find their target.

Subject of Research: KIF11 inhibition as a lineage-remodeling strategy to restore androgen receptor signaling and antiandrogen sensitivity in castration-resistant prostate cancer

Article Title: KIF11 inhibition remodels lineage state and sensitizes castration-resistant prostate cancer to antiandrogen therapy via enhancer–promoter looping

Article References: Deng, Z., He, L., Li, J., She, S., Luo, X., Lin, J., Qi, Z., Zhuang, Y., Gao, X., Chi, Z., Xu, Z., Ji, Y., Liu, J., Lin, S. L., & Cui, Y. (2026). KIF11 inhibition remodels lineage state and sensitizes castration-resistant prostate cancer to antiandrogen therapy via enhancer–promoter looping. Molecular Cancer. https://doi.org/10.1186/s12943-026-02792-6

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02792-6

Keywords: KIF11, castration-resistant prostate cancer, androgen receptor, lineage plasticity, enhancer-promoter looping, CTCF, epigenetics, enzalutamide, apalutamide, FOXA1, patient-derived organoids, drug resistance

Enhancers are regulatory DNA elements that can be located thousands or even hundreds of thousands of bases away from the promoters of the genes they regulate. Their activity depends in part on the formation of three-dimensional chromatin loops that allow enhancer-bound regulatory factors to contact promoter-bound transcription machinery. Although researchers have known that many enhancers produce short-lived transcripts called enhancer RNAs, or eRNAs, the precise role of these molecules has remained difficult to define. Promoter regions also generate nascent RNAs as transcription begins, creating an opportunity for RNA molecules from the two regulatory regions to interact. The new study proposes that hnRNPK recognizes and organizes these emerging transcripts, converting RNA–RNA contacts into a stable molecular bridge between enhancer and promoter.

Rather than functioning only as a conventional RNA-binding factor, hnRNPK appears to provide an architectural framework for transcriptional regulation. The researchers found that it binds preferentially to nascent RNAs produced from active enhancers and promoters. These RNAs are generated locally while the relevant chromatin regions are being transcribed, placing them close to the DNA sites that need to communicate. By associating with both classes of transcript, hnRNPK may concentrate enhancer- and promoter-derived RNAs in the same molecular environment. Such proximity could stabilize interactions between the RNAs and help fold the intervening chromatin into a loop. The model offers a mechanistic explanation for how transient RNA molecules can influence a much larger and more persistent structure in the genome.

The study further indicates that hnRNPK can assemble into phase-separated condensates. These are dynamic, concentrated compartments formed when proteins and nucleic acids cluster through numerous weak interactions rather than through a single permanent molecular bond. Phase separation is increasingly recognized as a way for cells to organize biochemical reactions without enclosing them in a membrane. In the case of hnRNPK, the condensates were described as containing cavities that encapsulate RNA polymerase II. This arrangement could create a specialized transcriptional environment in which regulatory RNAs, chromatin-associated factors and the polymerase are brought together at high local concentrations, making productive transcription more likely.

A particularly important feature of the proposed mechanism involves the RPB3 subunit of RNA polymerase II. The investigators report that hnRNPK interacts with Pol II through RPB3, providing a direct protein-based route for incorporating the transcriptional enzyme into hnRNPK condensates. Once Pol II is concentrated within these assemblies, enhancer-associated complexes may be able to influence its delivery to nearby or physically connected promoters. The researchers suggest that hnRNPK dimerization could contribute to this process: one portion of an hnRNPK assembly could engage enhancer-derived RNA and regulatory factors, while another connects with promoter-associated RNA and Pol II. In this framework, enhancer–promoter looping is not merely a passive consequence of chromatin folding but an active process coordinated by RNA-binding proteins.

This mechanism also helps explain why enhancer transcription may be functionally important even when eRNAs are rapidly degraded and do not encode proteins. Their role may depend less on their final abundance than on their production at the correct genomic location and time. As these RNAs emerge from the DNA, they can serve as temporary molecular signals or scaffolds for proteins such as hnRNPK. The resulting assemblies could integrate several signals at once, including the identity of the enhancer, the activity state of the promoter and the availability of Pol II. By linking these signals, hnRNPK may help ensure that developmental genes are activated only when the appropriate regulatory elements are engaged.

The biological significance of the findings was tested using a mutation in hnRNPK associated with Au–Kline syndrome, a rare developmental disorder. The mutation, designated c.953+1dupG, altered the physical properties of hnRNPK condensates. Instead of remaining liquid-like and dynamic, the mutant condensates became more gel-like. Liquid-like condensates can continuously exchange their molecular components with the surrounding nucleus, allowing them to assemble, reorganize and dissolve as transcriptional requirements change. A gel-like state may restrict this exchange, trapping components or preventing the rapid rearrangements required for enhancer–promoter communication. The results suggest that the material state of a condensate is not a cosmetic property but a critical determinant of gene regulation.

Knock-in mice carrying the disease-associated mutation developed developmental defects, providing evidence that the molecular changes have consequences at the level of the organism. Fibroblasts derived from these animals showed reduced enhancer–promoter looping and diminished recruitment of Pol II to the promoters of key developmental genes. These observations connect the mutation’s effects across several scales: it changes the physical behavior of hnRNPK condensates, weakens three-dimensional contacts between regulatory DNA elements, reduces transcriptional machinery at gene promoters and ultimately contributes to developmental abnormalities. The findings are consistent with the idea that many congenital disorders may result not only from loss of a protein’s biochemical activity but also from changes in the dynamics and material properties of nuclear assemblies.

The work presents hnRNPK as a general structural regulator of gene expression rather than a factor restricted to a small set of specialized genes. By mediating interactions between enhancer and promoter RNAs, organizing phase-separated condensates and engaging Pol II through RPB3, hnRNPK may provide a common platform for communication across the genome. The proposed model also broadens the view of noncoding transcription: RNAs produced from regulatory DNA may act as active architectural components, even when they do not persist as stable cellular molecules. Further research will be needed to determine how hnRNPK selects particular RNA sequences, how its condensates are regulated by signaling pathways and whether similar defects in condensate dynamics contribute to other human diseases. For now, the study identifies a molecular link between nascent RNA, chromatin looping and transcriptional activation, revealing how the genome’s distant control elements can work together with remarkable precision.

Subject of Research: hnRNPK-mediated enhancer–promoter looping, RNA–RNA interactions, phase-separated condensates and RNA polymerase II recruitment

Article Title: hnRNPK condensates facilitate enhancer–promoter looping and RNA polymerase II recruitment

Article References: Ye, R., Zhao, H., Chen, J. et al. hnRNPK condensates facilitate enhancer–promoter looping and RNA polymerase II recruitment. Nat Genet (2026). https://doi.org/10.1038/s41588-026-02710-y

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41588-026-02710-y

Keywords: hnRNPK, enhancer RNA, promoter RNA, enhancer–promoter looping, RNA polymerase II, phase separation, condensates, chromatin architecture, Au–Kline syndrome, gene regulation