Histone Modification and GBM Therapy

对化疗和放疗的抵抗是多形性胶质母细胞瘤患者的一大障碍。 因此，了解这些患者化疗-放射抵抗的机制是至关重要的。我们的 最近的发现使我们假设组蛋白甲基转移酶(HMT)MMSET是导致 放化疗。MMSET(也称为WHSC1，NSD2)已被证明对组蛋白H4甲基化 Lys20(H4K20)、H3 Lys27(H3K27)和H3 Lys36(H3K36)。除了几份将其链接到 在转录调控方面，MMSET的细胞功能仍然不清楚。我们发现MMSET 在DNA损伤反应中参与ATM-MDC1-53BP1通路。具体而言，MMSET 聚集在DNA损伤的部位。与此相关的是53BP1所需的H4K20甲基化 招募[1]，在DNA损伤部位也增加。MMSET的下调减少了H4K20 甲基化并取消53BP1向DNA损伤部位的积聚。这些结果表明 MMSET通过其HMT活性作为53BP1的上游调节因子发挥作用。以支持其在 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在部分胶质母细胞瘤细胞系中过表达，并且 MMSET与对替莫唑胺(TMZ)和辐射(RT)的耐药有关。基于这些 初步发现，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对化疗和放射治疗的敏感性(图1)。进一步研究 在这一假设下，我们提出了以下具体目标：1.DNA中MMSET的结构-功能分析 损伤反应；2.用小鼠模型研究MMSET在TMZ/RT反应中的作用；3.检查 GBM患者MMSET的表达及其与TMZ/RT反应的关系这些研究将 揭示了MMSET在细胞对遗传毒性应激反应中的新作用。此外，计划中的 翻译研究将确定MMSET是否是治疗反应的重要调节器 胶质母细胞瘤患者，这将提供关键的洞察为什么至少一些患者具有良好的 MGMT甲基化状态在化疗和放射治疗中进展不佳。

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.