Oral squamous cell carcinoma (OSCC) remains a formidable challenge within oncology, owing to its high prevalence and often late-stage diagnosis. Despite significant advances in cancer biology, the molecular events that propel preneoplastic lesions toward invasive OSCC have remained elusive, particularly regarding the epigenetic alterations that may serve as early triggers in tumorigenesis. A groundbreaking study published in the International Journal of Oral Science on April 17, 2025, now illuminates the critical role of lysine-specific demethylase 1 (LSD1) in dictating the fate of OSCC initiation and progression. This research, conducted collaboratively by teams led by Manish Bais at Boston University and colleagues at the University of Florida, unveils precise molecular mechanisms linking LSD1 activity to oncogenic and immunosuppressive pathways that promote tumor development.
Epigenetic regulation, through post-translational modifications of histone residues, orchestrates chromatin dynamics and gene expression profiles essential for cellular identity and homeostasis. LSD1 operates as a histone demethylase that selectively removes methyl groups from histone H3 at lysine 4 (H3K4) and lysine 9 (H3K9), modulating transcriptional programs that can either activate or repress gene expression. The study reveals that in early-stage OSCC, aberrant upregulation of LSD1 activity sustains oncogenic signaling cascades, notably via altering phosphorylation states of cyclin-dependent kinase 7 (CDK7), a pivotal factor in cell cycle progression and transcriptional regulation. By orchestrating CDK7 phosphorylation, LSD1 indirectly sustains the activation of Signal Transducer and Activator of Transcription 3 (STAT3), a well-known promoter of oncogenesis and immune evasion.
Using a combination of sophisticated genetic knockout models and pharmacological inhibition with specific LSD1 inhibitors such as SP2509, the research team demonstrated a notable suppression of OSCC preneoplastic progression. These interventions not only halted cellular proliferation but also induced a profound remodeling of the tumor microenvironment that favored anti-tumor immune responses. Most strikingly, LSD1 inhibition alleviated immunosuppressive barriers by downregulating CTLA4, a key checkpoint molecule that hinders CD8+ T cell function. The resulting augmented infiltration and activation of cytotoxic T lymphocytes underscore a dual mechanism whereby LSD1 inhibition simultaneously disrupts oncogenic signaling and reactivates host immunity.
The translational significance of these findings was further reinforced through a pioneering veterinary clinical trial employing Seclidemstat—a clinical stage LSD1 inhibitor—establishing both safety and efficacy in feline models of OSCC. Seclidemstat effectively suppressed STAT3 phosphorylation and mitigated tumor growth while amplifying immune cell infiltration. This trial provides critical proof-of-concept evidence that targeting LSD1 in early-stage oral preneoplasia is a viable therapeutic strategy and bridges preclinical findings with potential clinical applications.
Drilling deeper into the molecular underpinnings, the research delineates how LSD1-mediated histone demethylation tunes CDK7 activity via site-specific phosphorylation events. CDK7, as a component of the transcription factor TFIIH, participates in the phosphorylation of the RNA polymerase II C-terminal domain, thereby influencing global transcriptional elongation. The dysregulation of CDK7 in the context of enhanced LSD1 activity thus facilitates persistent STAT3 activation, fostering an environment conducive to epithelial transformation and immunosuppression. This novel axis connecting LSD1, CDK7 phosphorylation, and STAT3 signaling advances our mechanistic understanding of OSCC preneoplasia and identifies multiple nodal points for therapeutic intervention.
Immune evasion remains a hallmark of cancer progression, and the revelation that LSD1 inhibition diminishes CTLA4-mediated immunosuppression marks a significant milestone in the modulation of tumor-immune dynamics. The restoration of CD8+ T cell infiltration and effector functions upon LSD1 blockade suggests that epigenetic regulators critically modulate the immunological landscape of early OSCC lesions. By relieving the immune checkpoint constraints and invigorating anti-tumor immunity, LSD1 inhibitors present an appealing complementary approach to existing immunotherapies, potentially overcoming resistance mechanisms inherent in OSCC.
Furthermore, the study challenges the conventional paradigm that treats OSCC predominantly at invasive stages. The ability to intercept tumorigenesis at its preneoplastic inception by modulating epigenetic readers and writers portends a paradigm shift in oral oncology. Early therapeutic intervention leveraging LSD1 inhibitors could drastically reduce OSCC incidence and improve long-term survival, circumventing the morbidity associated with advanced disease and exhaustive treatments.
This investigation also propels the field of cancer epigenetics forward, emphasizing the nuanced roles of demethylases such as LSD1 in tumor progression outside of classical genetic mutations. Integrating epigenetic modulation with immune reactivation offers a multipronged strategy to disrupt the complex crosstalk between cancer cells and their microenvironment. The potential to combine LSD1 inhibitors with immune checkpoint blockade or other targeted agents opens exciting avenues for combination therapies aimed at durable tumor suppression.
Given the compelling evidence in both murine and feline models, future clinical trials in humans are poised to validate LSD1 inhibition as a cornerstone in early OSCC management. The ongoing development of potent, selective LSD1 inhibitors with favorable pharmacokinetic profiles will be critical to translating these findings into effective therapies. Moreover, identifying reliable biomarkers to stratify patients most likely to benefit from such interventions will optimize clinical outcomes.
Dr. Manish Bais and his team underscored the importance of this discovery by emphasizing how targeting the epigenetic machinery is not merely about halting tumor cell proliferation but also about restoring the intricate balance of immune surveillance that cancer subverts. The dual action of stopping tumor progression and reawakening effective anti-tumor immunity represents a sophisticated therapeutic advance that harnesses the body’s natural defenses in combating early oral cancer.
In conclusion, the elucidation of LSD1’s role in OSCC preneoplasia via modulation of CDK7 phosphorylation and STAT3 signaling, along with its impact on immunosuppression, presents a transformative understanding of oral carcinogenesis. The validation of LSD1 inhibitors like SP2509 and Seclidemstat as promising agents to reverse early neoplastic changes and boost anti-tumor immunity heralds a new era in precision oncology. Targeting the epigenetic control points in combination with immunomodulation may redefine OSCC prevention and treatment strategies, offering renewed hope to patients at risk of this devastating disease.
Subject of Research: Not applicable
Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression
News Publication Date: 17-Apr-2025
Web References: http://dx.doi.org/10.1038/s41368-025-00363-x
References: 10.1038/s41368-025-00363-x
Image Credits: international journal of oral science
Keywords: Oral cancer
Tags: cancer biology advancementschromatin dynamics and cancerearly-stage OSCC biomarkersepigenetics in oral cancerhistone modifications in cancerimmunosuppressive tumor environmentlysine-specific demethylase 1 roleoncogenic pathways in OSCCOSCC progression mechanismspreneoplastic lesions progressiontargeted therapies for oral cancertranscriptional regulation in tumors
