THOR hypermethylation and hTERT reactivation define an epigenetic axis in cervical cancer

Abstract Background Telomerase reactivation via hTERT upregulation drives cervical cancer progression, yet the epigenetic mechanisms remain poorly understood, particularly in India’s high-burden population. The TERT Hypermethylated Oncological Region (THOR) critically regulates hTERT transcription, but its functional role and clinical relevance are unexplored. Methods We analyzed hTERT expression, telomere length, THOR methylation, and HPV status in 100 cervical cancer and 50 control tissues. Functional validation employed 5-aza-2′-deoxycytidine (AZA) treatment in C-33 A, ME-180, HeLa, SiHa, and Saos-2 cells, with menin recruitment assessed by ChIP assays. Results hTERT expression and telomere length significantly elevated in cervical cancer, correlating with age, International Federation of Gynecology and Obstetrics (FIGO) stage, and menopausal status. THOR hypermethylation emerged as an independent epigenetic regulator of hTERT, operating regardless of clinicopathological parameters. Strikingly, HPV status showed no association with hTERT, telomere length, or THOR methylation, revealing HPV-independent epigenetic drivers. AZA treatment partially reversed hTERT upregulation and suppressed telomerase activity with cell line-specific responses. Menin enrichment was markedly reduced at hypermethylated THOR but restored upon hypomethylation, establishing a direct epigenetic-mechanistic link. Conclusion We provide first evidence that THOR epigenetic modulation drives telomere maintenance in Indian cervical cancer patients. Low menin recruitment to hypermethylated THOR identifies a novel epigenetic axis with dual prognostic and diagnostic potential. The HPV-independent nature of THOR regulation highlights an underexplored therapeutic target for epigenetic therapy in cervical cancer.