SUV Family Histone Methyltransferases Modulate Nuclear Lamin A and Drive Tumorigenesis: Integrative Pan-Cancer TCGA analysis and Experimental Evidence

Epigenetic regulation of chromatin structure is a key determinant of transcriptional control and nuclear organization in cancer. Among histone lysine methyltransferases, SUV39H1 and SUV39H2 catalyze the trimethylation of histone H3 lysine 9 (H3K9me3), establishing repressive heterochromatin domains that are essential for genomic stability. However, their pan-cancer expression dynamics, prognostic value, and structural implications remain poorly defined. In this study, we performed an integrative analysis of SUV39H1 and SUV39H2 across the Cancer Genome Atlas (TCGA) cohort to investigate their expression, prognostic relevance, associations with the immune landscape, and interactions with nuclear lamina genes. Both enzymes were significantly overexpressed in multiple tumor types, with SUV39H2 showing particularly high expression in high-grade serous ovarian cancer (HGSOC), where elevated levels correlated with poor overall survival (HR = 3.27, p < 0.001). Immune infiltration analysis revealed that high SUV39H2 expression was inversely associated with tumor-infiltrating lymphocytes, indicating an immunosuppressive tumor microenvironment. Correlation studies demonstrated strong positive associations between SUV39H1/H2 and Lamin B genes (LMNB1, LMNB2), implicating their role in maintaining nuclear architecture and heterochromatin tethering. Conversely, Lamin A (LMNA) exhibited weak or negative correlation with SUV39 enzymes. Functional validation in A2780 ovarian cancer cells demonstrated that pharmacological inhibition of SUV39H2 by Chaetocin resulted in the upregulation of Lamin A, indicating epigenetic repression of LMNA by SUV39H2. Collectively, our findings uncover a novel link between SUV39H2, chromatin–lamina interactions, and immune evasion in ovarian cancer, providing a rationale for targeting SUV39H2 in therapeutic epigenetic interventions.