The SIRT1–miR203a Axis in HPV-Associated Head and Neck Cancer: Epigenetic Regulation, Genome Instability and Immune Modulation
ProjectHuman papillomavirus-positive (HPV+) head and neck squamous cell carcinomas (HNSCCs) are steadily rising globally and represent
a major clinical issue, particularly among younger patients with long-term survival expectancy. Although HPV+ tumors generally
respond better to therapy than HPV-negative counterparts, current treatments still rely on highly toxic radio-chemotherapy regimens
associated with severe long-term morbidity and lower quality of life. Reliable biomarkers predicting therapy response and
progression remain limited.
This project investigates the SIRT1–miR203a regulatory axis as a novel epigenetic and translational vulnerability in HPV-associated
HNSCC. Preliminary data generated by the consortium demonstrate that pharmacological inhibition of SIRT1 selectively impairs
proliferation and survival of HPV-positive epithelial and HNSCC-derived cells through reactivation of the p53–p21 pathway, induction
of replication stress-associated mitotic defects and senescence. In parallel, miR203a, a tumor-suppressive microRNA frequently
downregulated in HPV-associated cancers, is restored following SIRT1 inhibition, suggesting a reversible SIRT1-dependent epigenetic
repression mechanism.
We hypothesize that aberrant SIRT1 activity promotes epigenetic silencing of miR203a, thereby sustaining chromatin plasticity,
replication stress adaptation and transcription-associated genome instability in HPV-driven tumors. We further propose that
deregulation of this axis contributes to R-loop accumulation, G-quadruplex formation and transcription–replication conflicts,
ultimately reshaping DNA damage responses, innate immune signaling and therapeutic sensitivity.
The project integrates complementary expertise in clinical oncology, molecular biology, immunology, chromatin biology and genome
instability research through a multidisciplinary consortium involving five operational units. Using HPV-positive and HPV-negative
cellular models, annotated patient-derived cohorts and preclinical systems, the consortium will combine transcriptomics, proteomics,
epigenetic profiling, DRIP-seq, BG4 ChIP-seq, mNET-seq and immune analyses to define the molecular and functional consequences
of SIRT1–miR203a deregulation. The project will additionally evaluate the therapeutic potential of SIRT1 inhibition and miR203a
restoration in combination with radiotherapy, cisplatin and PARP inhibitors in HPV-associated HNSCC models.
Through the integration of multi-omics analyses, immune profiling and clinically annotated patient-derived datasets, the project aims
to identify epigenetic, circulating and immune-associated biomarkers applicable to patient stratification and treatment monitoring.
The proposed research is expected to uncover previously unexplored vulnerabilities of HPV-associated HNSCC and establish the
basis for innovative biomarker-driven therapeutic strategies improving treatment efficacy while reducing long-term toxicity.
a major clinical issue, particularly among younger patients with long-term survival expectancy. Although HPV+ tumors generally
respond better to therapy than HPV-negative counterparts, current treatments still rely on highly toxic radio-chemotherapy regimens
associated with severe long-term morbidity and lower quality of life. Reliable biomarkers predicting therapy response and
progression remain limited.
This project investigates the SIRT1–miR203a regulatory axis as a novel epigenetic and translational vulnerability in HPV-associated
HNSCC. Preliminary data generated by the consortium demonstrate that pharmacological inhibition of SIRT1 selectively impairs
proliferation and survival of HPV-positive epithelial and HNSCC-derived cells through reactivation of the p53–p21 pathway, induction
of replication stress-associated mitotic defects and senescence. In parallel, miR203a, a tumor-suppressive microRNA frequently
downregulated in HPV-associated cancers, is restored following SIRT1 inhibition, suggesting a reversible SIRT1-dependent epigenetic
repression mechanism.
We hypothesize that aberrant SIRT1 activity promotes epigenetic silencing of miR203a, thereby sustaining chromatin plasticity,
replication stress adaptation and transcription-associated genome instability in HPV-driven tumors. We further propose that
deregulation of this axis contributes to R-loop accumulation, G-quadruplex formation and transcription–replication conflicts,
ultimately reshaping DNA damage responses, innate immune signaling and therapeutic sensitivity.
The project integrates complementary expertise in clinical oncology, molecular biology, immunology, chromatin biology and genome
instability research through a multidisciplinary consortium involving five operational units. Using HPV-positive and HPV-negative
cellular models, annotated patient-derived cohorts and preclinical systems, the consortium will combine transcriptomics, proteomics,
epigenetic profiling, DRIP-seq, BG4 ChIP-seq, mNET-seq and immune analyses to define the molecular and functional consequences
of SIRT1–miR203a deregulation. The project will additionally evaluate the therapeutic potential of SIRT1 inhibition and miR203a
restoration in combination with radiotherapy, cisplatin and PARP inhibitors in HPV-associated HNSCC models.
Through the integration of multi-omics analyses, immune profiling and clinically annotated patient-derived datasets, the project aims
to identify epigenetic, circulating and immune-associated biomarkers applicable to patient stratification and treatment monitoring.
The proposed research is expected to uncover previously unexplored vulnerabilities of HPV-associated HNSCC and establish the
basis for innovative biomarker-driven therapeutic strategies improving treatment efficacy while reducing long-term toxicity.