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