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Targeting the Calcineurin Homologous Protein 1 (CHP1)-Transmembrane Protein 87A (TMEM87A) mechanosensing complex: a
Ming-Zhu Jin1,2, Heng-An Liu3, Wen Di4,5
1Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Abstract:
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.
Insights
Calcineurin homologous protein 1 (CHP1) and transmembrane protein 87A (TMEM87A) regulate high-grade serous ovarian carcinoma (HGSC) metastasis. Sodium gluconate disrupts this complex, offering a potential therapeutic strategy for ovarian cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Metastatic high-grade serous ovarian carcinoma (HGSC) is largely incurable, with poor understanding of the molecular mechanisms driving intraperitoneal dissemination.
- Tumor cell survival during detachment (anoikis evasion) is critical for HGSC metastasis from the fallopian tube epithelium.
Purpose of the Study:
- Identify novel molecular mediators of HGSC metastasis.
- Investigate the role of calcineurin homologous protein 1 (CHP1) and its interaction with transmembrane protein 87A (TMEM87A) in HGSC progression.
- Evaluate sodium gluconate as a potential therapeutic agent targeting the CHP1-TMEM87A complex.
Main Methods:
- Integrative analysis of transcriptomic datasets to identify metastasis-associated genes.
- 3D spheroid models and in vivo orthotopic mouse models (NSG mice) to study tumor growth and metastasis.
- Bioinformatic analysis, co-immunoprecipitation, CETSA, MST, and SPR to elucidate molecular interactions and drug efficacy.
- Kaplan-Meier survival analysis of public datasets to assess clinical significance.
Main Results:
- CHP1 was identified as a novel mediator of HGSC metastasis, crucial for spheroid integrity and anoikis evasion.
- CHP1 interacts with TMEM87A, forming a putative mechanosensing complex regulating YAP-GPC6-WNT5A/Hedgehog signaling.
- Knockout of CHP1 or TMEM87A suppressed tumor growth and metastasis in vivo.
- Low-dose sodium gluconate disrupted CHP1-TMEM87A binding, inhibited Hedgehog signaling, and reduced tumor burden.
- High CHP1/TMEM87A expression showed stage-dependent prognostic significance in HGSC patients.
Conclusions:
- The CHP1-TMEM87A complex acts as a mechanosensitive regulator of HGSC metastasis.
- Targeting the CHP1-TMEM87A complex with gluconate represents a promising therapeutic strategy for ovarian cancer.
- CHP1 and TMEM87A expression levels have prognostic implications in different stages of HGSC.
