Targeting the Calcineurin Homologous Protein 1 (CHP1)-Transmembrane Protein 87A (TMEM87A) mechanosensing complex: a druggable vulnerability in metastatic ovarian cancer

Despite advances in treatment, metastatic high-grade serous ovarian carcinoma (HGSC) remains largely incurable, and the molecular machinery enabling tumor cells to survive detachment and disseminate intraperitoneally remains poorly understood. HGSC metastasis requires tumor cells to evade anoikis during detachment from the fallopian tube epithelium. Through integrative analysis of hyaluronic acid (HA) metabolism-associated genes in transcriptomic datasets, calcineurin homologous protein 1 (CHP1) was identified as a novel mediator of HGSC metastasis. Mechanistically, CHP1 ablation disrupted spheroid morphogenesis in 3D models, inducing aberrant multi-spheroid formation and reduced structural integrity, with impaired cell extrusion from mosaic spheroids. Bioinformatic and experimental validation revealed that CHP1 interacted with the mechanosensitive channel transmembrane protein 87A (TMEM87A), forming a putative mechanosensing complex that may regulate metastasis via the YAP–GPC6–WNT5A/Hedgehog signaling axis; knockout of either gene downregulated WNT5A/GPC6 and inhibited WNT5A/Hedgehog pathways. In vivo, CHP1 or TMEM87A knockout significantly suppressed orthotopic tumor growth and metastasis in NSG mice, indicating a role in overall tumor progression beyond metastasis alone. Drug repurposing identified sodium gluconate (a TMEM87A modulator) as a therapeutic candidate: low-dose treatment (1 mg/kg, weekly) significantly reduced tumor burden by disrupting CHP1-TMEM87A binding and inhibiting downstream Hedgehog/PTCH1 signaling, as the cellular thermal shift assay (CETSA), microscale thermophoresis (MST), surface plasmon resonance (SPR), and co-immunoprecipitation. Clinically, high CHP1/TMEM87A expression exhibited stage-dependent prognostic significance (favorable in early-stage, unfavorable in late-stage HGSC), as assessed by Kaplan–Meier survival analysis of publicly available datasets. These findings suggest that the CHP1-TMEM87A complex may serve as a mechanosensitive regulator of HGSC metastasis and propose gluconate-based targeting as a promising therapeutic strategy.