Oral squamous cell carcinoma (OSCC) progresses from seemingly benign preneoplastic lesions, but understanding the epigenetic triggers for this transition remains limited. A new study reveals lysine-specific demethylase 1 (LSD1) as a crucial player in OSCC initiation. The researchers show that inhibiting LSD1 in early-stage lesions, through either genetic knockout or pharmacological agents like SP2509, prevents tumor growth, restores immune function, and halts the progression of OSCC. This groundbreaking research highlights LSD1 inhibition as a potential therapeutic strategy for intercepting OSCC before it becomes invasive, offering new hope for early detection and intervention.
Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths, and early detection is key to improving patient outcomes. However, the mechanisms driving the transition from preneoplastic lesions to full-blown cancer are not well understood. Previous research has primarily targeted advanced OSCC, overlooking the early stages of tumor progression. The new study focuses on lysine-specific demethylase 1 (LSD1), an epigenetic regulator that plays a significant role in OSCC development. By unraveling the molecular pathways through which LSD1 influences the tumor microenvironment, the study offers crucial insights into early-stage cancer biology and paves the way for innovative treatment strategies targeting this epigenetic modifier.
A study (DOI: 10.1038/s41368-025-00363-x) published in International Journal of Oral Science (2025) on April 17, 2025, uncovers the pivotal role of LSD1 in the progression of oral cancer. The multidisciplinary research from Manish Bais's laboratory at Boston University and the University of Florida, Drs. Sahay and Takada,, found that inhibiting LSD1, either through genetic modifications or the pharmacological agent SP2509, reversed OSCC preneoplasia and enhanced immune cell infiltration. These findings not only deepen our understanding of OSCC biology but also suggest that LSD1 inhibition could serve as a promising therapeutic strategy to prevent the progression of OSCC from preneoplastic stages, potentially transforming early-stage oral cancer treatment.
The study demonstrates that LSD1, an epigenetic regulator, plays a central role in the development of OSCC by controlling critical signaling pathways such as STAT3 and CDK7. The research team employed both genetic knockout models and pharmacological agents like SP2509 to inhibit LSD1 activity, revealing that this intervention effectively reversed the progression of OSCC preneoplasia in murine and feline models. Key observations included a reduction in tumor growth, the restoration of immune function through enhanced CD8+ T cell infiltration, and decreased levels of the immunosuppressive CTLA4 protein. In a novel veterinary clinical trial, the researchers found that Seclidemstat, a clinical candidate for LSD1 inhibition, was both safe and effective in inhibiting STAT3 signaling, further validating the translational potential of LSD1-targeted therapies. This study's findings underscore the importance of epigenetic regulation in OSCC progression and highlight the therapeutic potential of LSD1 inhibitors in preventing the transition from preneoplastic lesions to malignant tumors.
"Understanding how epigenetic regulators like LSD1 drive the progression of oral cancer which has been evaluated over several years in our lab, offers us new opportunities to intervene at a much earlier stage," said Dr. Manish Bais, lead senior author of the study. "Our findings demonstrate that targeting LSD1 not only halts tumor growth but also restores critical immune responses that can enhance anti-tumor immunity against cancer.. These results open up exciting possibilities for treating preneoplasia before it becomes OSCC and could ultimately improve patient survival rates."
The implications of this study are far-reaching, as inhibiting LSD1 could offer a new avenue for the treatment of OSCC. By targeting the early stages of tumor progression, LSD1 inhibitors, such as Seclidemstat, could provide a means to prevent OSCC before it becomes invasive, offering a significant breakthrough in early-stage cancer management. Additionally, the study suggests that combining LSD1 inhibition with existing immunotherapies could enhance immune responses and overcome tumor-induced immunosuppression. As clinical trials continue to investigate these therapies, LSD1 inhibition has the potential to reshape the treatment landscape for OSCC and other cancers driven by similar epigenetic mechanisms.
