Histone Modification and GBM Therapy

组蛋白修饰和 GBM 治疗

• 批准号: 8729254
• 负责人: JOSEPH C LOFTUS
• 金额: $ 13.38万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729254
• 关键词: Affect; Biological Markers; Cell physiology; Cells; Clinical; DNA Damage; Disease; Down-Regulation; Drug Targeting; Etiology; Genotoxic Stress; Glioblastoma; Hereditary Disease; Histone H4; Histones; Lead; Link; MGMT gene; Malignant neoplasm of brain; Methylation; Methyltransferase; Multiple Myeloma; Pathway interactions; Patients; Prognostic Marker; Radiation; Radioresistance; Reporting; Resistance; Role; Sampling; Site; Structure; Syndrome; Testing; Transcriptional Regulation; WHSC1 gene; Wolf-Hirschhorn Syndrome; Xenograft Model; base; chemoradiation; chemotherapy; histone methyltransferase; histone modification; human disease; insight; malformation; mouse model; novel; overexpression; promoter; protein protein interaction; radiation resistance; response; temozolomide; translational study; treatment response; tumorigenesis

Resistance to chemotherapy and radiation is a big obstacle for patients with glioblastoma multiforme (GBM) Therefore, it is critical to understand mechanisms responsible for chemo-radioresistance these patients. Our recent findings led us to hypothesize that the histone methyltransferase (HMT) MMSET is a contributor to chemoradioreslstance. MMSET (also called WHSC1, NSD2) has been shown to methylate histone H4 Lys20 (H4K20), H3 Lys27 (H3K27) and H3 Lys36 (H3K36). Besides several reports linking it to transcriptional regulation, the cellular function of MMSET remains obscure. We found that MMSET participates in the ATM-MDC1-53BP1 pathway during the DNA damage response. Specifically, MMSET accumulates at sites of DNA damage. Correlating with this, H4K20 methylation, which is required for 53BP1 recruitment [1], also increases at the sites of DNA damage. Downregulation of MMSET decreases H4K20 methylation and abolishes the accumulation of 53BP1 to the sites of DNA damage. These results suggest that MMSET functions as an upstream regulator of 53BP1 through its HMT activity. In support of its role in DNA damage responses, MMSET affects cellular sensitivity to temozolomide (TMZ) and radiation (RT). Finally, we found that MMSET is overexpressed in a subset of glioblastoma lines, and overexpression of MMSET is associated with resistance to temozolomide (TMZ) and radiation (RT). Based on these preliminary findings, we hypothesize that MMSET regulates 53BP1 and the TMZ/RT response, and that misregulation of MMSET could affect GBM sensitivity to chemo-radiotherapy (Figure 1). To further examine this hypothesis, we propose the following Specific Aims: 1. Structure-function analysis of MMSET in the DNA damage response; 2. Investigate the role of MMSET in TMZ/RT response using mouse models; 3. Examine the expression of MMSET in GBM patients and its correlation with TMZ/RT response. These studies will reveal a novel role of MMSET in cellular response to genotoxic stress. Furthermore, the planned translational studies will define whether MMSET is an important modulator of treatment response for glioblastoma patients, which would provide key insight into why at least some patients with a favorable MGMT methylation status fare poorly with chemo-radiotherapy.

对化疗和放疗的耐药性是多形性胶质母细胞瘤（GBM）患者的一大障碍 因此，了解这些患者化疗放疗耐药的机制至关重要。我们的 最近的研究结果使我们推测组蛋白甲基转移酶 (HMT) MMSET 是 化学放射抗性。 MMSET（也称为 WHSC1、NSD2）已被证明可使组蛋白 H4 甲基化 Lys20 (H4K20)、H3 Lys27 (H3K27) 和 H3 Lys36 (H3K36)。除了几份将其链接到 转录调控，MMSET 的细胞功能仍然不清楚。我们发现MMSET 在 DNA 损伤反应过程中参与 ATM-MDC1-53BP1 通路。具体来说，MMSET 在 DNA 损伤部位积累。与此相关的是 53BP1 所需的 H4K20 甲基化 DNA 损伤部位的募集 [1] 也会增加。 MMSET 的下调降低了 H4K20 甲基化并消除 53BP1 在 DNA 损伤位点的积累。这些结果表明 MMSET 通过其 HMT 活性发挥 53BP1 上游调节器的作用。支持其在以下方面的作用 DNA 损伤反应，MMSET 影响细胞对替莫唑胺 (TMZ) 和辐射 (RT) 的敏感性。 最后，我们发现 MMSET 在胶质母细胞瘤系的一个子集中过度表达，并且 MMSET 与替莫唑胺 (TMZ) 和辐射 (RT) 耐药性相关。基于这些 根据初步结果，我们假设 MMSET 调节 53BP1 和 TMZ/RT 反应，并且 MMSET 的失调可能会影响 GBM 对放化疗的敏感性（图 1）。进一步检查 根据这一假设，我们提出以下具体目标： 1. DNA 中 MMSET 的结构功能分析 损害反应； 2. 使用小鼠模型研究MMSET在TMZ/RT反应中的作用； 3. 检查 GBM患者中MMSET的表达及其与TMZ/RT反应的相关性。这些研究将 揭示了 MMSET 在细胞对基因毒性应激反应中的新作用。此外，计划中的 转化研究将确定 MMSET 是否是治疗反应的重要调节剂 胶质母细胞瘤患者，这将提供关键的见解，为什么至少有一些患者具有良好的 MGMT 甲基化状态在放化疗中表现不佳。