Aug 2026· Proceedings of the National Academy of Sciences of the United States of America· Vol 123 35, pp.
e2401248123
· 0 citations· 42 references
Medicine
TL;DR
Findings indicate that, by decreasing RBPs, while inducing DNA damage and ISR, SRI-42127 reduces HPV oncoproteins, restores p53 function in HPV+ CaCxs, thereby enhancing their sensitivity to conventional chemotherapy.
Abstract
High-risk human papillomaviruses (HR-HPVs) cause 95% of cervical cancers (CaCx) and a significant fraction of other anogenital and oropharyngeal cancers. Transcriptomic analyses have revealed that HR-HPVs differentially induce RNA binding proteins (RBPs) associated with cancer-related pathways. One of them, ELAVL2/HuB, is related to the ubiquitous, well-studied ELAVL1/HuR. But the role of either RBP in HPV pathobiology is unclear. In this study, we examined SRI-42127, an inhibitor of HuR, for its ability to curb CaCx growth in multiple model systems. We report that HR-HPV E6 and E7 oncogenes regulate the abundance and localization of HuB and HuR, that these two RBPs form a heterodimer, and that their genes are transcriptionally linked. We show that SRI-42127 reduces both RBPs, disrupts cell cycle regulation, and induces apoptosis in CaCx cell lines. We attribute these effects to a previously unrecognized ability to induce DNA damage and integrated stress response (ISR), resulting in decreased HPV E6 and E7 transcripts and proteins, while stabilizing transcriptionally active p53. Using siRNA knockdown, our results confirm that the reduction of HuB and HuR causes DNA damage and induces ISR. Furthermore, SRI-42127 curtails tumor growth of HPV16+/hRasG12V transformed mouse TC-1 cells in syngeneic mice. Additionally, SRI-42127 complements cisplatin in inhibiting the growth of a CaCx cell line in 3D cultures and patient-derived xenografts in SCID mice. Collectively, these findings indicate that, by decreasing RBPs, while inducing DNA damage and ISR, SRI-42127 reduces HPV oncoproteins, restores p53 function in HPV+ CaCxs, thereby enhancing their sensitivity to conventional chemotherapy.
Persistent infection with high-risk human papillomaviruses (HPVs), notably HPV-16 and HPV-18, underlies most cervical cancers and many head and neck cancers. Here, we report the structural and functional basis by which the viral oncoprotein E7 hijacks host CRL2ZER1 to degrade retinoblastoma (Rb) protein and drive E2F-dependent proliferation. Crystal structures reveal that the N-terminal MH/N-degron of E7 engages a defined pocket within the armadillo (ARM)-repeat domain of ZER1. Disruption of this interface abolishes E7-ZER1 binding, prevents Rb degradation, silences E2F transcriptional programs, and impairs proliferation of HPV-positive cancer cells. Guided by these insights, we identify a first-in-class small-molecule inhibitor that blocks E7-ZER1 association, restores Rb stability, and selectively suppresses HPV-positive tumor growth in vivo. These results define a viral mimicry mechanism and nominate the ZER1 degron pocket as a ligandable therapeutic target for HPV-driven malignancies, highlighting translational opportunities for targeted therapy.
Understanding Human papillomavirus (HPV) oncogenic mechanisms is essential for developing preventive and therapeutic strategies and overcoming therapy resistance in HPV-related cancers. These challenges may arise from the ability of high-risk HPV to subvert host tumor suppressors such as p53 and Rb, and to drive oncogenesis through homologous recombination deficiency (HRD) and multi-network dysregulation. Mechanistically, HPV exerts context-dependent effects on the host DNA damage response (DDR). During episomal replication, E6/E7 activate DDR and recruit BRCA1/RAD51 to replication foci to support viral replication without significantly compromising host HR repair. Upon viral integration, however, sustained E6/E7 expression drives HRD and shifts DNA repair toward error-prone end joining, generating genomic instability that fuels malignant transformation. These alterations are most clearly established in cervical cancer, whereas evidence in HPV-positive non-cervical cancer is more variable and requires further context-specific validation. In parallel, HPV E6/E7 antagonize transforming growth factor-β (TGF-β)-mediated tumor suppression and, potentially through FAT Atypical Cadherin 4 (FAT4) down-regulation, engage Wnt/β-catenin signaling. The resultant elevation of nuclear β-catenin induces programmed death-ligand 1 (PD-L1) expression promotes immune evasion, stemness, and invasiveness. Of note, while the DDR-TGF-β-β-catenin-PD-L1 axis is backed by substantial evidence in HPV-related cancers, certain connections within this pathway are extrapolated from non-HPV models or general pathway biology and are explicitly denoted as such in the main text. With residual p53 activity, HRD may confer initial sensitivity to DNA-damaging agents, but resistance frequently develops—a pattern reminiscent of the initial response followed by acquired resistance observed with immunotherapies in HPV-related cancers. Integrating these mechanistic insights, we propose ablative therapies (e.g., ablation, photodynamic therapy, surgery) for cervical intraepithelial neoplasia (CIN), and for advanced or resistant disease, a synthetic-lethality framework combining genotoxic therapies with DDR inhibitors, targeting DDR-TGF-β-β-catenin-PD-L1 axis, and antiviral approaches. The proposed therapeutic strategies, however, should be interpreted with caution, as their evidence base varies across tumor types and warrants further investigation.
Wei Liu, Shanmei Chen, Li-Wei Wang et al.· Frontiers in Immunology· 0 citations
Aim: Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors, such as oropharyngeal cancers, highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. Therefore, this study aimed to evaluate the expression of HPV16 oncogenes E5, E6, and E7 in breast tumors, as well as the modulation of the PI3K/AKT/mTOR signaling pathway associated with viral activity. Methods: A total of 92 breast cancer patients were included after Ethics Committee approval. Clinical data were obtained from medical records. RNA was extracted from formalin-fixed, paraffin-embedded tissues and reverse-transcribed into cDNA. Transcripts of HPV oncogenes (E5, E6, and E7), components of the PI3K/AKT/mTOR pathway, and regulatory genes (EGFR and PTEN) were quantified by RT-qPCR. Gene expression levels were calculated using the ΔCt method. Results: Forty-eight samples met RNA quality criteria and were included in the expression analysis. Among these, 77.08% showed expression of at least one viral oncogene, with E5 being the most frequently expressed. The PI3K/AKT/mTOR pathway was modulated in HPV-positive samples, with increased PI3K expression and decreased mTOR expression. Notably, the high expression of E5—associated with immune evasion—combined with reduced mTOR expression suggests that HPV16 status may influence therapeutic response in breast cancer patients. Conclusions: These findings reinforce the importance of further studies investigating HPV activity in breast tumors to better understand its biological and clinical impact.
Beatriz Eda de Oliveira Isídio, Pedro Henrique Bezerra Fontes, Gabriel Rômulo Parente da Silva et al.· Exploration of Targeted Anti...· 1 citation
BACKGROUND
Cervical cancer (CC) is a prevalent malignancy in women. RNA-binding motif single-stranded interacting protein 3 (RBMS3) acts as a tumor suppressor in many cancer types, but its role and underlying regulatory mechanisms in CC remain unclear.
METHODS
The expression levels of RBMS3 and heat shock protein family A member 6 (HSPA6) were evaluated in clinical CC tissues. Gain- and loss-of-function assays, transcriptome sequencing, and rescue experiments were performed in CC cell lines and nude mouse xenograft models.
RESULTS
RBMS3 expression was notably lower in CC tissues (n = 306) than in normal cervical tissues (n = 22), with reduced levels linked to shorter overall patient survival (p < 0.05). Overexpression of RBMS3 reduced cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo (p < 0.001). HSPA6 was identified as a key target of RBMS3 and was also downregulated in CC tissues. RBMS3 potentially binds to HSPA6 mRNA and enhances its stability. Knockdown of HSPA6 reversed the tumor-suppressive effects of RBMS3 (p < 0.001).
CONCLUSIONS
RBMS3 inhibits CC progression by stabilizing HSPA6 mRNA. The RBMS3-HSPA6 axis may represent a prognostic biomarker and therapeutic target in CC.
Hua-Ping Huang, Ping Li, Lixia Zhu et al.· Frontiers in Bioscience· 0 citations
It is indicated that chrysin treatment is associated with selective cytotoxicity and concurrent modulation of HPV16 E6 protein levels and several cancer-related miRNAs in CaSki cells.
Mahdis Gholami Fashkhami, Hadi Habibollahi, Seyedeh Tooba Shafighi· Medical Oncology· 0 citations
Cervical cancer remains a major cause of cancer-related morbidity and mortality in women worldwide. Although HPV18-positive tumors are frequently associated with aggressive clinicopathological behavior, the redox-linked mechanisms by which HPV18 drives cervical cancer progression remain incompletely defined. Here, integrated clinical, multi-omics, biochemical, and in vivo analyses were performed to delineate the role of HPV18-E7 in ferroptosis regulation. In the TCGA-CESC cohort, HPV18 positivity was associated with inferior progression-free survival and disease-free survival and was enriched in adenocarcinoma-related histology. Functionally, HPV18-E7 promoted cervical cancer cell proliferation and suppressed RSL3-induced ferroptotic death, lipid peroxidation, ferrous iron accumulation, and clonogenic loss. Integrated transcriptomic, proteomic, and metabolomic profiling identified ferroptosis defense, oxidative phosphorylation, glutathione/redox homeostasis, sulfur amino acid metabolism, and lipid remodeling as convergent pathways downstream of HPV18-E7. A lipid-focused re-analysis identified 41 features that met VIP > 1 and P < 0.05 in both knockdown comparisons and changed concordantly, of which 20 also met q < 0.05 in both comparisons. Reciprocal co-immunoprecipitation confirmed associations of HPV18-E7 with HSPA5 and of HSPA5 with GPX4. HPV18-E7 stabilized HSPA5 protein by attenuating K48-linked ubiquitination and proteasomal turnover, and thereby maintained GPX4 abundance. MG132, but not chloroquine under the tested condition, attenuated the loss of the HSPA5/GPX4 module after HPV18-E7 depletion, supporting a predominant proteasomal contribution in this setting. Gain- and loss-of-function rescue experiments established HSPA5 as a required downstream effector of HPV18-E7-mediated GPX4 maintenance and ferroptosis resistance. In a HeLa xenograft model, HPV18-E7 depletion markedly enhanced the antitumor efficacy of the ferroptosis inducer RSL3, accompanied by increased MDA and 4-HNE signals and reduced Ki67 and SCD1 expression. Collectively, these findings identify an HPV18-E7/HSPA5/GPX4 axis that promotes cervical cancer progression by preserving ferroptosis resistance, while lipid remodeling provides a complementary metabolic component of the phenotype.
