bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–11–02
fifteen papers selected by
Valentina Piano, Uniklinik Köln
  1. Nucleosome interaction of the CPC secures centromeric chromatin integrity and chromosome segregation fidelity.
  2. Meteorin Is a Novel Interaction Partner of p60-Katanin During Mitosis in HCT-116 Colorectal Cancer Cells.
  3. Coiled-coil interactions drive the ectopic condensation of overexpressed MAD1 to promote mitotic slippage in cancer cells.
  4. Spindle localization of YAP/TAZ maintains even distribution of YAP/TAZ in daughter cells.
  5. Functional stability of the second mitotic spindle in blastomeres and its association with multinucleation repair.
  6. Oocyte checkpoint response to the spindle poison depends on the cytoplasm volume.
  7. Dissociation of the nuclear basket triggers chromosome loss in aging yeast.
  8. KDM4A serves as an α-tubulin demethylase regulating microtubule polymerization and cell mitosis.
  9. Roles of Srs2/PARI-family DNA helicases in NoCut checkpoint signaling and abscission regulation.
  10. How augmin establishes the angle of the microtubule branch site.
  11. Chromatin remodeling activity of EP400 safeguards chromosomal stability by preventing CENP-A mislocalization.
  12. Phospho-Tau Signature During Mitosis: AT8, p-T217 and p-S422 as Key Phospho-Epitopes.
  13. Insects evolved a monomeric histone-fold domain in the CENP-T protein family.
  14. KMT2C inactivation leads to PTEN downregulation and tolerance to DNA damage during cell cycle progression.
  15. Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe.
  1. EMBO J. 2025 Oct 27.
    Nucleosome interaction of the CPC secures centromeric chromatin integrity and chromosome segregation fidelity.
    Anjitha Gireesh, Maria Alba Abad, Ryu-Suke Nozawa, Paula Sotelo-Parrilla, Léa C Dury, Mariia Likhodeeva, Martin Wear, Christos Spanos, Cristina Cardenal Peralta, Juri Rappsilber, Karl-Peter Hopfner, Marcus D Wilson, Willem Vanderlinden, Toru Hirota, A Arockia Jeyaprakash.
      The chromosomal passenger complex (CPC; Borealin-Survivin-INCENP-Aurora B kinase) ensures accurate chromosome segregation by orchestrating sister chromatid cohesion, error correction of kinetochore-microtubule attachments, and spindle assembly checkpoint signaling. Correct spatiotemporal regulation of CPC is critical for its function. Phosphorylations of histone H3 Thr3 and histone H2A Thr120 and modification-independent nucleosome interactions involving Survivin and Borealin contribute to CPC centromere enrichment. However, how various nucleosome binding elements collectively contribute to CPC centromere enrichment at the mechanistic level, and whether CPC has any non-catalytic role at centromere remain open questions. Combining the high-resolution cryo-EM structure of a CPC-bound H3Thr3ph nucleosome with atomic force microscopy and biochemical and cellular assays, we demonstrate that CPC employs multipartite interactions, which facilitate its engagement with nucleosome acidic patch and the DNA entry-exit site. Perturbing the CPC-nucleosome interaction compromises chromatin protection against MNase digestion in vitro, and centromeric chromatin stability and error-free chromosome segregation in cells. Our work suggests a non-catalytic chromatin-stabilizing role of CPC in maintaining centromeric chromatin features critical for kinetochore function.
    Keywords:  Centromere Integrity; Chromosomal Passenger Complex; Chromosome Segregation; Kinetochore; Mitosis
    DOI:  https://doi.org/10.1038/s44318-025-00594-y
  2. Cytoskeleton (Hoboken). 2025 Oct 29.
    Meteorin Is a Novel Interaction Partner of p60-Katanin During Mitosis in HCT-116 Colorectal Cancer Cells.
    Ilgin Isiltan, Arzu Karabay.
      Microtubule cytoskeletal proteins are essential for maintaining cellular functions. In addition to dynamic instability, the organization of the microtubule cytoskeleton is also regulated by microtubule-severing proteins, which play roles in critical processes such as cell division. One of the microtubule-severing proteins, p60-Katanin, localizes to the mitotic spindle, centrosomes, midbody, and contractile ring, thereby facilitating the proper completion of the cell cycle, which requires microtubule remodeling. Here, we identify Meteorin as a novel interaction partner of p60-Katanin in HCT-116 colorectal cancer (CRC) cells. Meteorin is observed to localize at spindle poles during prophase, metaphase, anaphase, and telophase in cell division. Our findings also indicate that Meteorin co-localizes with p60-Katanin during mitosis. Silencing of Meteorin leads to reduced cell proliferation irrespective of TP53 expression in both HCT-116 and HCT-116 p53 (-/-) CRC cells. Upon Meteorin silencing, p60-Katanin expression decreases in both CRC cell types, whereas it increases due to Meteorin overexpression in only HCT-116 CRC cells. Overall, these results indicate that Meteorin localizes to spindle poles and interacts with p60-Katanin, and that depletion of Meteorin inhibits the proliferation of HCT-116 CRC cells regardless of p53 expression.
    Keywords:  HCT 116; meteorin; microtubule; mitosis; p60‐katanin; proliferation
    DOI:  https://doi.org/10.1002/cm.70059
  3. iScience. 2025 Oct 17. 28(10): 113638
    Coiled-coil interactions drive the ectopic condensation of overexpressed MAD1 to promote mitotic slippage in cancer cells.
    Jason Tones, Jasper Jeffrey, Rachel M Lackner, David M Chenoweth, Huaiying Zhang.
      The mitotic checkpoint protein MAD1 is overexpressed in cancers, weakening the mitotic checkpoint and promoting mitotic slippage. Overexpressed MAD1 forms ectopic foci in mitotic cells, but the biophysical nature of these foci and their roles in mitotic slippage remain unclear. Here, we report that MAD1 ectopic foci are phase-separated condensates that shorten mitosis by sequestering checkpoint proteins. We show that MAD1 ectopic foci display dynamic condensate behaviors, and Mad1 phase separation is driven by interactions between its coiled-coil and disordered domains at the N-terminus. By inducing MAD1 ectopic condensates in mitotic cells with low MAD1 levels, we decouple the effects of condensation from concentration and demonstrate the causal role of condensation in mitotic slippage. Mechanistically, MAD1 ectopic condensates trap the diffusive pool of MAD2, weakening the MAD2 conversion cycle needed for a robust checkpoint. Our work highlights a loss of function caused by ectopic condensates in cancer cells.
    Keywords:  Biochemistry; Biological sciences; Cancer; Cell biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2025.113638
  4. J Biosci. 2025 ;pii: 78. [Epub ahead of print]50
    Spindle localization of YAP/TAZ maintains even distribution of YAP/TAZ in daughter cells.
    Yuxing Huang.
      YAP and TAZ are downstream effectors of the Hippo signaling pathway, known to shuttle between the cytoplasm and nucleus, where they primarily function as transcriptional coactivators. Although their nuclear role has been well characterized, the non-transcriptional functions of YAP/TAZ remain poorly understood. In this study, we report that YAP/TAZ localize to the metaphase spindle in a microtubule-dependent manner. Specifically, we demonstrate that YAP interacts with α-tubulin via its WW domain. Notably, while the spindle localization of YAP/TAZ does not affect the mechanics of mitotic cell division, it does influence the distribution of YAP/TAZ protein levels between the resulting daughter cells. These findings reveal a novel, nontranscriptional role for YAP/TAZ during mitosis.
  5. F S Sci. 2025 Oct 23. pii: S2666-335X(25)00079-5. [Epub ahead of print]
    Functional stability of the second mitotic spindle in blastomeres and its association with multinucleation repair.
    Taichi Sakaguchi, Hiromitsu Shirasawa, Yuki Ono, Kazumasa Takahashi, Mayumi Goto, Motonari Okabe, Chika Ariake, Akari Tsuya, Takeo Hirakawa, Takuya Iwasawa, Ayaka Fujishima, Yohei Onodera, Tae Sugawara, Kenichi Makino, Hiroshi Miura, Noritaka Fukunaga, Yoshimasa Asada, Yukiyo Kumazawa, Yukihiro Terada.
       OBJECTIVE: To study mitotic spindle morphology and chromosomal segregation in second mitosis.
    DESIGN: Live-cell imaging of DNA and tubulin during the second mitosis of 21 freeze-thawed human two-pronuclear (2PN) stage embryos was performed to analyze spindle morphology and chromosome segregation dynamics. Furthermore, chromosomal aneuploidy was assessed in all cells of the embryos that developed to the blastocyst stage.
    SUBJECTS: Twenty-one freeze-thawed human 2PN embryos.
    EXPOSURE: We analyzed live-imaging videos of DNA and microtubules during the second division of 21 human 2-cell embryonic blastomeres. We further analyzed the association between the results of pre-implantation genetic testing for aneuploidy (PGT-A) of all cells in the observed embryos after development into blastocysts and the nuclear status at the early embryonic stage.
    MAIN OUTCOME MEASURES: Spindle morphology during the second mitosis, chromosomal segregation patterns, nuclear status of daughter blastomeres, and chromosomal aneuploidy of all cells in blastocysts derived from the observed embryos.
    RESULTS: Multinucleation rate in daughter nuclei was significantly lower after the second than after the first mitosis (22% vs. 56%: p = 0.03). Neither defocusing of spindle poles-which was prominent in first mitosis-nor chromosomal segregation abnormalities, such as misalignment of metaphase chromosomes and lagging chromosomes during chromosomal segregation, were observed. There was no association between the nuclear status at the 2- and 4-cell stages of the observed embryos that had progressed to the blastocyst stage and the PGT-A results of all cells in the blastocysts.
    CONCLUSION: Observations of mitotic spindle morphology and chromosomal segregation behavior revealed that second mitosis is less prone to chromosomal segregation errors than first mitosis. This suggests that segregation errors occurring during the first mitosis may be corrected during second mitosis. Furthermore, there was no association between the nuclear status during early embryonic divisions and the chromosomal status of blastocyst cells, suggesting the presence of a mechanism that corrects chromosomal abnormalities during early development.
    Keywords:  Human embryonic development; embryo evaluation; multinucleation; second mitosis; spindle dynamics
    DOI:  https://doi.org/10.1016/j.xfss.2025.10.003
  6. Syst Biol Reprod Med. 2025 Dec;71(1): 538-548
    Oocyte checkpoint response to the spindle poison depends on the cytoplasm volume.
    Regina Daszkiewicz, Łukasz Gąsior, Katarzyna Kotarska, Zbigniew Polanski.
      The embryonic aneuploidy in mammals may arise from impaired Spindle Assembly Checkpoint (SAC) function, a mechanism which prevents errors in chromosome segregation by blocking anaphase in response to spindle anomalies. Mammalian oocytes are particularly susceptible to these errors, possibly because the large oocyte volume favors dilution of the checkpoint signal, preventing its efficient function. This study aimed to investigate hypothesis that oocyte cytoplasmic volume affects SAC functionality. Oocyte size was manipulated in prophase oocytes (before nuclear envelope breakdown, NEBD) or in M-phase oocytes (after NEBD) by either reducing or increasing cytoplasmic volume by half. These oocytes were then cultured in the presence of nocodazole which activated the SAC by arresting oocytes in metaphase I of the first meiotic division. The functionality of SAC was assessed by measuring the proportion of oocytes escaping SAC-induced metaphase I arrest and completing the first meiotic division i.e., extruding the first polar body and entering the metaphase II of the second meiotic division. Reduction of the cytoplasmic volume in the prophase stage resulted in stronger checkpoint function, with only 4% of oocytes escaping SAC arrest compared to 36% of control normal-sized oocytes. Conversely, enlarged oocytes showed diminished checkpoint efficiency, with 54% bypassing checkpoint-induced arrest compared to 20% of control normal-sized oocytes. Importantly, no such relationship was observed when cytoplasmic volume was altered in oocytes after NEBD. This may suggest that the SAC depends on some nucleus-associated factors that are released into the cytoplasm after NEBD, since such factors would be twice as concentrated in oocytes undergoing volume reduction before NEBD compared to those undergoing reduction after NEBD. These results prove that SAC efficiency in mouse oocytes is influenced by cytoplasmic volume, with larger volumes impairing its function.
    Keywords:  Spindle Assembly Checkpoint; aneuploidy; mouse female meiosis; nocodazole; nuclear factors; oocyte size
    DOI:  https://doi.org/10.1080/19396368.2025.2576084
  7. Elife. 2025 Oct 30. pii: RP104530. [Epub ahead of print]14
    Dissociation of the nuclear basket triggers chromosome loss in aging yeast.
    Mihailo Mirkovic, Jordan McCarthy, Anne Cornelis Meinema, Julie Parenteau, Sung Sik Lee, Sherif Abou Elela, Yves Barral.
      In many organisms, aging is a clear risk factor for chromosome missegregation, the main source of aneuploidy. Here, we report that old yeast cells lose chromosomes by partitioning them asymmetrically to their daughter cells together with the pre-existing (old) spindle pole body (SPB, centrosome equivalent in yeast). Strikingly, remodelling of the nuclear pore complex (NPC) and the displacement of its nuclear basket triggered these asymmetric chromosome segregation events. Simultaneously, nuclear basket displacement caused unspliced pre-mRNAs to leak into the cytoplasm. We show that removing the introns of three genes involved in chromosome segregation was sufficient to fully suppress chromosome loss in old cells. Promoting pre-mRNA leakage in young cells also caused asymmetric chromosome partitioning and loss through the same three introns. Therefore, we propose that basket displacement from NPCs and its consequences for pre-mRNA quality control are key triggers of aging phenotypes such as aneuploidy.
    Keywords:  NPC; RNA; S. cerevisiae; aging; aneuploidy; cell biology; chromosomes; gene expression; intron; mitosis
    DOI:  https://doi.org/10.7554/eLife.104530
  8. Sci Adv. 2025 Oct 31. 11(44): eadv6637
    KDM4A serves as an α-tubulin demethylase regulating microtubule polymerization and cell mitosis.
    Suhao Cao, Shaogang Wang, Xuan Xie, Xinyi Tan, Xinyu Hu, Fengxia Shao, Yanling Liu, Xu Zhang, Hong Cheng, Lei Diao, Lan Bao.
      Posttranslational modifications of tubulin give microtubule distinct properties to support diverse cellular functions. Trimethylation on lysine-40 of α-tubulin (α-TubK40me3) is involved in cell division and neuronal development. The "writer" (SETD2) and "reader" (PBRM1) of α-TubK40me3 have been identified. However, the "eraser" of α-TubK40me3 and the impact of α-TubK40me3 dynamic balance on cells are still unclear. Here, we report that KDM4A, a member of the histone demethylase family, binds α-tubulin through its catalytic core domain and demethylates α-tubulin. KDM4A knockout significantly enhances α-TubK40me3, inducing microtubule polymerization and mitotic defects. Furthermore, the overpolymerized microtubules and cell mitotic defects caused by KDM4A knockout are rescued by reducing α-TubK40me3 with overexpression of an α-tubulin mutant α-tubulinK40A or depolymerizing microtubules with nocodazole treatment in cells. Together, our study identifies KDM4A as an α-tubulin demethylase, and this demethylation is important for regulating microtubule polymerization and cell mitosis.
    DOI:  https://doi.org/10.1126/sciadv.adv6637
  9. J Cell Biol. 2025 Dec 01. pii: e202502014. [Epub ahead of print]224(12):
    Roles of Srs2/PARI-family DNA helicases in NoCut checkpoint signaling and abscission regulation.
    Monica Dam, David F Moreno, Nicola Brownlow, Audrey Furst, Coralie Spiegelhalter, Manuel Mendoza.
      The coordination of chromosome segregation with cytokinesis is crucial for maintaining genomic stability. Chromatin bridges, arising from DNA replication stress or catenated chromosomes, can interfere with this process, leading to genomic instability if not properly resolved. Here, we uncover that the budding yeast DNA helicase Srs2 is essential for delaying abscission in the presence of chromatin bridges, thereby preventing chromosome breakage during cytokinesis. We also find that its human paralog PARI delays abscission-associated events, including midbody severing and actin-patch disassembly, in human cells with chromatin bridges. Although PARI depletion does not lead to increased bridge breakage or binucleation, our data indicate that PARI has nonessential functions within the Aurora B-mediated abscission checkpoint pathway. These findings establish a key role of Srs2 in NoCut checkpoint signaling in yeast, and suggest a functionally related role of PARI in coordinating abscission timing with chromatin bridge resolution in human cells.
    DOI:  https://doi.org/10.1083/jcb.202502014
  10. Nat Commun. 2025 Oct 31. 16(1): 9646
    How augmin establishes the angle of the microtubule branch site.
    Sophie M Travis, Jodi Kraus, Collin T McManus, Kiana Golden, Rui Zhang, Sabine Petry.
      How microtubules (MTs) are generated in the proper orientation is essential to understanding how the cytoskeleton organizes a cell and MT-dependent events such as cell division. In the spindle, most MTs are generated through the branching MT nucleation pathway. In this pathway, new MTs are nucleated from the side of existing MTs and oriented at a shallow angle by the branching factor augmin, ensuring that both MTs have the same polarity. Yet, how augmin binds MTs and sets the branch angle has remained unclear. Here, we report the cryo-electron microscopy structure of an augmin subcomplex on the MT. This structure resembles that of NDC80 bound to the MT, with the conserved CH domain of augmin's Haus6 subunit directly proximal to the MT lattice. We find that the Haus6 CH domain is a bona fide MT binding site that increases augmin's affinity for the MT and helps establish branch angle. A second binding site, located in the disordered N-terminus of Haus8, also establishes branch angle,. Thus, we find that augmin regulates MT branching using two domains, each tuned to modulate MT affinity and MT branch angle. This work expands our mechanistic understanding of branching MT nucleation and thus spindle formation.
    DOI:  https://doi.org/10.1038/s41467-025-64650-1
  11. Cell Rep. 2025 Oct 24. pii: S2211-1247(25)01194-5. [Epub ahead of print]44(11): 116423
    Chromatin remodeling activity of EP400 safeguards chromosomal stability by preventing CENP-A mislocalization.
    Subhash Chandra Sethi, Roshan L Shrestha, Vinutha Balachandra, Tetsuya Hori, Luca Corda, Shinjen Lin, Laurent Ozbun, Tatiana S Karpova, Katherine McKinnon, Raj Chari, Gianluca Pegoraro, Ken Chih-Chien Cheng, Simona Giunta, Natasha J Caplen, Tatsuo Fukagawa, Munira A Basrai.
      The mislocalization of CENP-A to non-centromeric regions contributes to chromosomal instability (CIN). The NuA4 histone acetyltransferase complex members EP400 and KAT5 regulate histone H2A.Z-H2B exchange and acetylation of histones, respectively. Overexpression of CENP-A and mutations in NuA4 components are observed in cancers. Here, we define a role for the chromatin remodeling activity of EP400, a top hit in RNAi screens for increased nuclear levels of CENP-A, in preventing CENP-A mislocalization and CIN. Mechanistically, we demonstrate a defect in the extraction of CENP-A from chromatin in cells expressing the EP400K1085G mutant, which lacks ATPase activity for histone exchange. Consistent with these results, EP400K1085G cells show increased CENP-A enrichment in chromatin and mislocalization to non-centromeric regions. Importantly, EP400K1085G cells exhibit CIN phenotypes in stable, near-diploid RPE1 cells with wild-type p53. In summary, our findings expand the role of EP400 from nucleosome destabilization for histone exchange to preventing the stable association of CENP-A with non-centromeric regions and CIN.
    Keywords:  ATPase activity; CENP-A; CP: Molecular biology; EP400; KAT5; NuA4 HAT complex; centromere; chromatin remodeler; chromosomal instability; histone acetylation; kinetochore
    DOI:  https://doi.org/10.1016/j.celrep.2025.116423
  12. Cells. 2025 Oct 21. pii: 1638. [Epub ahead of print]14(20):
    Phospho-Tau Signature During Mitosis: AT8, p-T217 and p-S422 as Key Phospho-Epitopes.
    Marion Goussard, Kelly Zarka, Morgane Denus, Thomas Curel, Sylvie Claeysen, Bruno Lefebvre, Malika Hamdane, Philippe Marin, Julien Villeneuve, Marie-Laure Parmentier.
      Tau was initially identified as a microtubule-binding protein critical for microtubule stabilization. It is also a pathological hallmark of tauopathies, a group of neurodegenerative diseases that include Alzheimer's disease. Under pathological conditions, Tau becomes hyperphosphorylated at numerous sites and aggregates into filamentous deposits, contributing to neuronal cell death and disease progression. While significant research has focused on Tau phosphorylation dynamics and their consequences in pathological contexts, comparatively few studies have investigated Tau phosphorylation during physiological processes, despite the potential relevance to the early onset of pathology. Previous findings have suggested similarities between mitotic Tau phosphorylation and hyperphosphorylation observed in tauopathies, particularly at sites such as AT8, PHF1, S214, and S422. In this study, we quantified the relative levels of phosphorylation at 12 Tau phospho-epitopes during interphase and mitosis in vitro to establish a preliminary mitotic phospho-Tau signature, which was subsequently validated in vivo. Our results demonstrated pronounced phosphorylation of Tau at AT8, p-T217, and p-S422 epitopes during mitosis, both in vitro and in vivo. These findings provide new insights into the physiological phosphorylation of Tau and its potential links to pathological processes.
    Keywords:  Alzheimer’s disease; biomarker; mitosis; tauopathy
    DOI:  https://doi.org/10.3390/cells14201638
  13. EMBO Rep. 2025 Oct 29.
    Insects evolved a monomeric histone-fold domain in the CENP-T protein family.
    Sundar Ram Sankaranarayanan, Jonathan Ulmer, Anna Mørch, Ahmad Ali-Ahmad, Nikolina Sekulić, Ines Anna Drinnenberg.
      The histone-fold domain (HFD) is a conserved protein interaction module that requires stabilization through a handshake interaction with an HFD partner. All HFD proteins known to date form obligate dimers to shield the extensive hydrophobic residues along the HFD. Here, we find that the lepidopteran kinetochore protein CENP-T is soluble as a monomer. We attribute this stability to a structural rearrangement, which leads to the repositioning of the HFD helix α3. This brings a conserved two-helical extension closer to the histone fold, where it takes over the position and function of the CENP-T partner CENP-W. This change has no effect on the DNA-binding ability of the lepidopteran CENP-T. Our analysis suggests that the monomeric HFD originated in the last common ancestor of insects, with a possible second independent origin in Acariformes, both of which lack CENP-W. Our study highlights an unexpected structural variation in a protein module as conserved and optimized as the HFD, providing a unique perspective on the evolution of protein structure and the forces driving it.
    Keywords:  CCAN; Kinetochore; Lepidoptera; Mitosis
    DOI:  https://doi.org/10.1038/s44319-025-00603-5
  14. NPJ Precis Oncol. 2025 Oct 28. 9(1): 336
    KMT2C inactivation leads to PTEN downregulation and tolerance to DNA damage during cell cycle progression.
    Theodoros Rampias, Andreas Goutas, Dimitris Karagiannis, Zoi Kanaki, Antigoni Makri, Lorena Hoxhallari, Fotini E Koukouzeli, Varvara Paraskevopoulou, Dimitra Tsouraki, Nikolaos Paschalidis, Margaritis Avgeris, Andreas Scorilas, Apostolos Klinakis.
      Uncontrolled proliferation, resistance to apoptosis, inability to maintain genome integrity, and, recently, epigenetic reprogramming are all hallmarks of cancer. A number of gene expression and cell signaling networks control these-often-interconnected processes, while the study of their deregulation is in the forefront of cancer research for decades. Here we present data from cells and patients indicating that KMT2C, one of the most frequently mutated proteins in solid malignancies, is involved in all these processes. Its loss, a bad prognosis marker in bladder cancer, is associated with activation of the PI3K/PDK/AKT oncogenic/antiapoptotic axis, and tolerance to DNA damage during cell cycle progression. On the other hand, these cells suffer from mitotic stress that can be therapeutically exploited. Treatment with a PLK1 inhibitor showed high efficacy in vivo, and was associated with mitotic catastrophe and cellular senescence, providing evidence that targeting genes that promote mitotic progression could be a promising therapeutic approach in the subset of tumors with KMT2C loss.
    DOI:  https://doi.org/10.1038/s41698-025-01101-6
  15. Sci Rep. 2025 Oct 31. 15(1): 38188
    Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe.
    Jessica Teitel, Margaret Farah, Michele L Dziubinski, Pil Lee, Andrew White, Alexander Sobeck, Jose Colina, John Takyi-Williams, Bo Wen, Elmar Nurmemmedov, Ivan Babic, Andre Monteiro da Rocha, Karan Bedi, Aaron Robida, Grace McIntyre, Takashi Hotta, Yinzhi Lin, Sreeja C Sekhar, Ryoma Ohi, Analisa DiFeo.
      MYC overexpression is a well-established cancer vulnerability, yet direct therapeutic targeting of Myc remains a challenge. Here, we identify DL78 as a potent antimitotic agent with selective anticancer activity through its regulation of Myc. DL78 demonstrated broad efficacy by inhibiting growth across nine cancer types and significantly reducing tumor burden in an in vivo model of platinum-resistant high-grade serous ovarian cancer, with no overt toxicity. DL78 preferentially targets chromosomally unstable, MYC-overexpressing cancer cells, a hallmark of high-grade serous ovarian cancer. Mechanistically, DL78 exploits Myc's role in mitotic entry by disrupting its interaction with α-tubulin, leading to sustained mitotic arrest, mitotic catastrophe, and apoptosis while sparing nonmalignant cells. This study establishes a novel paradigm for Myc-targeted therapy by introducing DL78, which induces cancer-selective mitotic catastrophe by disrupting Myc's interaction with α-tubulin rather than its transcriptional activity.
    Keywords:  G2-M arrest; High-grade serous ovarian cancer; Mitotic catastrophe; c-Myc; α-tubulin
    DOI:  https://doi.org/10.1038/s41598-025-22011-4
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