SPC25

SPC25 is a core subunit of the NDC80 kinetochore complex that is required for chromosome alignment, spindle formation, and spindle assembly checkpoint signaling, established during mouse oocyte meiosis where both overexpression and knockdown disrupted chromosome alignment and spindle architecture (PMID:21084868). Within this complex, SPC25 physically engages its kinetochore partner NUF2 (PMID:39755832). Beyond this canonical mitotic/meiotic role, SPC25 functions as a scaffolding platform in cancer: it nucleates an SPC25/RIOK1/MYH9 trimeric complex in which RIOK1 phosphorylates MYH9 at Ser1943, driving nuclear MYH9 accumulation, CTNNB1 transcription, and Wnt/β-catenin activation that promotes cancer stem cell phenotypes and platinum resistance (PMID:39488790). SPC25 also stabilizes the transcription factor E2F1 by binding MDM2 and blocking MDM2-mediated E2F1 ubiquitination, leading to CCND1 upregulation and tumor progression (PMID:39919356). SPC25 promotes metabolic reprogramming, activating glutamine metabolism to enable immune escape from NK cell killing (PMID:40552366, PMID:39829079) and driving glycolysis to suppress ferroptosis (PMID:39558547). Its expression is directly activated at the promoter level by the transcription factors TFDP1 and E2F8 (PMID:40552366, PMID:39829079).

1. 2010 Medium

   Established SPC25 as a functional component of the NDC80 kinetochore complex by showing it is required for chromosome alignment, spindle formation, and checkpoint signaling, defining its core cell-division role.

   Evidence mRNA overexpression, siRNA knockdown, and immunofluorescence localization in mouse oocytes

   PMID:21084868

   Open questions at the time

   • Did not resolve molecular interfaces with other NDC80 subunits in this system
   • Restricted to meiotic oocytes; mitotic contribution not directly tested here
2. 2022 Medium

   Connected SPC25 to oncogenic integrin signaling, showing it promotes metastasis through ITGB4 and downstream FAK/PI3K/AKT phosphorylation.

   Evidence siRNA knockdown, microarray profiling, ITGB4 rescue, migration assays, and mouse model in HCC

   PMID:35293598

   Open questions at the time

   • Mechanism by which SPC25 upregulates ITGB4 not defined
   • No direct SPC25–integrin physical link shown
3. 2022 Low

   Linked SPC25 to DNA-PK/AKT/Notch1 signaling and stemness transcription (SOX2, NANOG) in HCC, extending its role to self-renewal control.

   Evidence knockdown/overexpression, western blot, and transcriptional reporter assays in HCC cell lines

   PMID:36147467

   Open questions at the time

   • No direct binding evidence placing SPC25 in this pathway; activation inferred indirectly
   • No reconstitution
4. 2024 Medium

   Defined SPC25 as a scaffold that assembles the SPC25/RIOK1/MYH9 complex, mechanistically linking it to Wnt/β-catenin activation and platinum resistance.

   Evidence reciprocal Co-IP, competitive peptide disruption, phospho-MYH9(Ser1943) blotting, nuclear fractionation, organoids and in vivo assays in ovarian cancer

   PMID:39488790

   Open questions at the time

   • Structural basis of the trimeric assembly not resolved
   • Whether scaffolding is independent of kinetochore function unclear
5. 2024 Low

   Identified PLEK2 as a direct SPC25 interactor and placed SPC25 within PI3K/AKT-dependent lung adenocarcinoma malignancy.

   Evidence single Co-IP, knockdown, proliferation/migration assays, xenograft

   PMID:38894536

   Open questions at the time

   • Single Co-IP without reciprocal validation
   • Direct SPC25-to-PI3K/AKT mechanistic link not demonstrated
6. 2024 Low

   Showed SPC25 drives the Warburg effect to suppress ferroptosis, positioning it upstream of glycolysis in a metabolic survival pathway.

   Evidence overexpression/knockdown, Seahorse, lipid ROS/Fe2+/MDA flow cytometry, 2-DG pharmacological rescue in prostate cancer

   PMID:39558547

   Open questions at the time

   • No direct binding or reconstitution for the SPC25–glycolysis link
   • Mechanism of glycolytic activation unknown
7. 2025 Low

   Demonstrated SPC25–NUF2 physical interaction is required for NSCLC growth, invasion, and glycolysis, reinforcing the functional importance of the kinetochore partnership in cancer.

   Evidence Co-IP, FISH, qRT-PCR, western blot, NUF2 rescue, xenograft

   PMID:39755832

   Open questions at the time

   • No reconstitution of the interaction
   • Whether glycolytic effect is a kinetochore-dependent function unclear
8. 2025 Medium

   Established direct transcriptional control of SPC25 by TFDP1 and E2F8 and linked SPC25-driven glutamine metabolism to suppression of NK cell anti-tumor immunity and immune escape.

   Evidence ChIP and dual-luciferase reporter assays, glutamine metabolism assays, NK co-culture/killing assays in lung adenocarcinoma

   PMID:39829079 PMID:40552366

   Open questions at the time

   • How SPC25 mechanistically activates glutamine metabolism not defined
   • Relationship between transcriptional regulators not integrated
9. 2025 Medium

   Defined a mechanism by which SPC25 stabilizes E2F1 by binding MDM2 and blocking its ubiquitination, driving CCND1-dependent tumor progression.

   Evidence Co-IP, ubiquitination assays, CCND1 rescue, in vitro/in vivo assays and IHC in esophageal squamous cell carcinoma

   PMID:39919356

   Open questions at the time

   • Structural basis of SPC25–MDM2 binding not resolved
   • Whether SPC25 affects other MDM2 substrates not tested

• How SPC25's canonical kinetochore role mechanistically relates to its diverse scaffolding, protein-stabilization, and metabolic functions in cancer remains unresolved.
• No structural model integrating kinetochore versus scaffold functions
• Unclear whether oncogenic functions require kinetochore localization
• No unifying mechanism connecting the multiple signaling and metabolic outputs