bims-midomi 2025-11-16 papers

Biosci Rep. 2025 Nov 12. pii: BSR20253646. [Epub ahead of print]

Reduced structural rigidity of MDMX protein enhances binding to TP53 mRNA.

Martina Kucerikova, Ondrej Bonczek, Vanesa Olivares-Illana, Andres Rodriguez-Rodriguez, Jose G Sampedro, Lenka Hernychova, Vaclav Hrabal, Pavlina Zatloukalova, Radovan Krejcir, Robin Fahraeus, Philip J Coates, Borivoj Vojtesek, Lucia Martinkova.

The two murine double minute (MDM) family members, MDM2 and MDMX are a well-established negative regulator of p53 activity. Under DNA damage conditions, MDM2 and MDMX are phosphorylated near their RING domains (serine 395 at MDM2 and serine 403 at MDMX) and switch to act as p53 positive regulators. MDMX binds to TP53 mRNA and acts as a chaperone for RNA structure, enabling MDM2 to bind. This interaction enhances TP53 mRNA translation, leading to increased p53 protein production. While the biological significance of this interaction has been described, the specific features of the MDMX-RNA interaction remain poorly understood. We used various MDMX protein constructs to characterize binding to TP53 mRNA and identified that the interaction mediated by the RING domain is modulated by the presence of other domains. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) and binding assays in high salt conditions and various pH demonstrate that the whole protein participates in RNA interaction, with the C-terminal domain likely providing the contact with RNA by electrostatic forces. We show that protein structural changes induced by the chelating agent EDTA or the reducing agent TCEP enhances RNA binding by promoting partial structural destabilization of the protein. Our findings suggest that the MDMX/TP53 mRNA interaction is complex, with the RING domain binding to RNA and being supported by the entire protein, which acts as a scaffold for the RNA interaction. These results contribute to a better understanding of MDMX´s role in TP53 mRNA binding and provide valuable insights for future investigation of the MDM2-MDMX-TP53 mRNA complex, which is crucial for p53 stabilization and activation under DNA-damaging conditions.

Keywords: TP53mRNA; HDX-MS mapping; MDMX-RNA interaction; RING domain

DOI: https://doi.org/10.1042/BSR20253646

Curr Opin Oncol. 2025 Oct 31.

State of the art and future directions in the treatment of metastatic adenoid cystic carcinoma.

Rachel Galot, Jean-Pascal H Machiels.

PURPOSE OF REVIEW: Metastatic adenoid cystic carcinoma (ACC) remains a therapeutic challenge with no approved systemic standard of care. This review highlights recent advances in ACC biology and emerging therapeutic strategies that may improve outcomes for patients with advanced disease.
RECENT FINDINGS: Recent progress in understanding the molecular biology of ACC has led to the investigation of novel systemic therapies. Recent studies have focused on targeted agents and immuno-oncology approaches. VEGFR-targeting tyrosine kinase inhibitors, such as lenvatinib and axitinib, have shown encouraging disease control rates and are now considered standard options. Immunotherapy has demonstrated limited efficacy. New agents targeting oncogenic drivers, such as NOTCH1 mutations and epigenetic regulators like PRMT5, have demonstrated preliminary activity in early-phase clinical trials. Additional strategies, including B7-H4 targeted antibody-drug conjugates, MYB-directed vaccines and degraders, and MDM2 inhibitors for TP53 wild-type tumors, offer strong biological rationale for further development.
SUMMARY: While conventional chemotherapy and immune checkpoint inhibitors remain largely ineffective, advances in ACC biology have driven the development of mechanism-based treatments. Future trials should prioritize biomarker-guided patient selection, rational combinations, and integration of molecular diagnostics to improve outcomes in this indolent but ultimately fatal disease.

Keywords: adenoid cystic carcinoma; immunotherapy; metastatic adenoid cystic carcinoma; salivary gland cancer; targeted therapy

DOI: https://doi.org/10.1097/CCO.0000000000001204

Adv Sci (Weinh). 2025 Nov 11. e17563

XPC Deficiency Activate Cisplatin-Mediated Autophagy in Bladder Cancer by Limiting Novel PHRF1-Mediated Ubiquitination of the p53 Protein.

Baixiong Zhao, Yaqin Huang, Jiazhong Shi, Xiaozhou Zhou, Johan Bourghardt Fagman, Liwei Wang, Sha Liu, Wuxing Wang, Yuting Liu, Zhiwen Chen, Jin Yang.

Muscle-invasive bladder cancers (MIBC) are biologically heterogeneous and have widely variable conventional chemotherapy responses and clinical outcomes. This study demonstrates that XPC deficiency in bladder cancer cells can promote autophagy in response to the cisplatin-mediated DNA damage response (DDR). This process is closely related to both the overexpression of KDM4A and the downregulation of PHRF1 induced by the overactivation of ATM phosphate. The overaccumulation of KDM4A can suppress PHRF1 expression and result in significant nuclear accumulation of the p53 protein. Notably, this study defines a new mechanism by which PHRF1 regulates p53 posttranslationally through the ubiquitin-proteasome system. In XPC low expression cells, PHRF1 performs a more critical E3 ubiquitin ligase function than MDM2. Especially under conditions of cisplatin-mediated DNA damage where MDM2 function is impaired, PHRF1 retains its functionality. In a mouse xenograft model, combining a KDM4 inhibitor with cisplatin results in superior antitumor effects compared with cisplatin alone. These findings provide new insights into the phenotypic plasticity of bladder cancer under drug resistance and highlight the potential of KDM4A inhibition and preservation of PHRF1 function in overcoming cisplatin resistance. Therefore, KDM4A or PHRF1 may be potential novel targets for the treatment of bladder cancer.

Keywords: PHRF1; XPC; autophagy; bladder cancer; drug resistance; p53

DOI: https://doi.org/10.1002/advs.202517563

Cureus. 2025 Oct;17(10): e94365

A Case of Rare Adipocytic Tumor of the Tongue: Lipoblastoma-Like Tumor With RB1 Gene Deletion.

Yoshihiko Sugita, Hiromasa Hasegawa, Rita R Roy, Katsumitsu Shimada, Takanaga Ochiai, Motohiko Nagayama, Hatsuhiko Maeda.

Lipoblastoma-like tumors (LLTs) are benign adipocytic tumors characterized by an admixture of lipoblasts within the myxoid stroma, primarily affecting the vulvovaginal area in young patients. Rare cases have been reported in other locations, including the orofacial region. Here, we present a unique case of LLT of the tongue in a 62-year-old woman with a slowly developing painless nodule. The tumor showed no signs of recurrence five years after surgery. Histopathological examination revealed a myxo-fatty lobulated lesion with numerous uni- and multi-vacuolated lipoblasts and prominent chicken-wire capillaries. Immunohistochemistry showed positivity for S100, whereas the tumor was negative for cluster of differentiation 34 (CD34), pleomorphic adenoma gene 1 (PLAG1), B-cell lymphoma 2 (BCL-2), mouse double minute 2 homolog (MDM2), cyclin-dependent kinase 4 (CDK4), and DNA damage-inducible transcript 3 (DDIT3). The retinoblastoma protein (pRB) was partially negative and exhibited mosaic patterns. Fluorescence in situ hybridization (FISH) analysis indicated a hemizygous deletion of the RB1 locus in 36% of tumor cells, with no MDM2 amplification detected. This case highlights the diagnostic challenges of differentiating LLTs from spindle cell lipomas (SCLs), particularly in the context of pRB deficiency and RB1 deletion. This case exemplifies the molecular heterogeneity of neoplasms with lipoblastoma-like features.

Keywords: cd34; differential diagnosis; lipoblastoma-like tumor; oral adipocytic tumors; plag1; rb1 deletion; retinoblastoma protein; spindle cell lipoma; tongue

DOI: https://doi.org/10.7759/cureus.94365

Dermatol Pract Concept. 2025 Oct 01. 15(4):

GRWD1 Drives Melanoma Growth Through NF-κB Signaling Pathway.

Dursun Turkmen, Rafet Ozbey, Berna Ozdem, Saadet Alan, Ayten Kilincli Cetin, Fatma Bengisu Baran, Berat Dogan, Nihal Altunisik, Zekiye Kanat, Serpil Sener, Ibrahim Tekedereli.

INTRODUCTION: Melanoma is an aggressive skin cancer with high metastatic potential. The oncogenic protein GRWD1 has been implicated in various cancer types, but its role in melanoma remains unclear.
OBJECTIVES: To examine the effects of GRWD1 knockdown on melanoma cell proliferation, apoptosis, and migration and to evaluate its prognostic significance in melanoma patients.
METHODS: A combination of in vitro and clinical analyses was performed. A2058 melanoma cells were treated with GRWD1-specific siRNA, and cell proliferation, apoptosis, and migration assays were conducted. Western blotting was used to assess alterations in key oncogenic pathways. Additionally, clinical tissue samples from melanoma patients were analyzed for GRWD1 expression, and Kaplan-Meier survival analysis was performed to determine its prognostic value.
RESULTS: GRWD1 was highly expressed in melanoma cells. GRWD1 knockdown significantly reduced cell proliferation (by 63%), impaired colony formation, and induced apoptosis (cleaved caspase-3 levels increased by 17.3%). Migration capacity decreased by 70%, and NF-κB pathway activity was suppressed, leading to reduced expression of Bcl-2, Src, and MDM2, while stabilizing p53. TCGA-based analyses revealed that high GRWD1 expression was significantly associated with shorter survival in metastatic melanoma cases (P=0.00029) but showed no correlation with melanoma subtypes. However, in immunohistochemical analysis of clinical samples, no statistically significant correlation was found between GRWD1 staining intensity and survival.
CONCLUSIONS: GRWD1 plays a crucial role in melanoma progression by enhancing NF-κB activity, promoting proliferation, and suppressing apoptosis. While high GRWD1 expression is associated with poor prognosis in public datasets, further clinical validation with larger patient cohorts is needed to confirm its utility as a prognostic biomarker and therapeutic target.

DOI: https://doi.org/10.5826/dpc.1504a5918