CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：SUV family histone methyltransferases correlate with nuclear lamina remodeling and clinical outcome in cancer: integrative pan-cancer TCGA analysis and experimental evidence.
SUV family histone methyltransferases correlate with nuclear lamina remodeling and clinical outcome in cancer: integrative pan-cancer TCGA analysis and experimental evidence.
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染色质结构的表观遗传调控是癌症中转录控制和核组织的关键决定因素。在组蛋白赖氨酸甲基转移酶中，SUV39H1和SUV39H2催化组蛋白H3赖氨酸9的三甲基化（H3K9me3），建立对基因组稳定性重要的抑制性异染色质结构域。
然而，它们的泛癌表达动态、预后价值及结构意义仍定义不清。在本研究中，我们对癌症基因组图谱（TCGA）队列中的SUV39H1和SUV39H2进行了整合分析，以研究其表达、预后相关性、与免疫景观的关联以及与核纤层基因的相互作用。两种酶在多种肿瘤类型中均显著过表达，其中SUV39H2在高grade浆液性卵巢癌（HGSOC）中表现出特别高的表达，其升高水平与较差的总生存期相关（HR = 3.27，p < 0.001）。免疫浸润分析显示，高SUV39H2表达与TIL（肿瘤浸润淋巴细胞）呈负相关，表明免疫浸润减少。相关性研究显示SUV39H1/H2与Lamin B基因（LMNB1、LMNB2）之间存在强正相关，提示与核纤层连接的异染色质相关。相反，Lamin A（LMNA）与SUV39酶表现出弱相关或负相关。在A2780卵巢癌细胞中的功能验证表明，通过Chaetocin对SUV39H2进行药理学抑制导致Lamin A上调，提示SUV39H1/H2抑制与Lamin A调控相关。
总体而言，我们的发现揭示了SUV39H2、染色质-核纤层相互作用与卵巢癌免疫逃逸之间此前未被充分认识的联系，突出表明SUV39H2是潜在的染色质相关生物标志物及核组织调控因子，并为在治疗性表观遗传干预中靶向SUV39H2提供了依据。
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 important 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 reduced immune infiltration.
Correlation studies demonstrated strong positive associations between SUV39H1/H2 and Lamin B genes (LMNB1, LMNB2), suggesting an association with nuclear lamina-linked heterochromatin. 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, suggesting that SUV39H1/H2 inhibition is associated with Lamin A regulation.
Collectively, our findings uncover a previously underappreciated association between SUV39H2, chromatin-lamina interactions, and immune evasion in ovarian cancer, highlighting SUV39H2 as a potential chromatin-associated biomarker and regulator of nuclear organization and providing a rationale for targeting SUV39H2 in therapeutic epigenetic interventions.
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