MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents.
MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents.
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DOI：
10.1038/onc.2016.116
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发表时间：
2016-11-10
期刊：
影响因子：
8
通讯作者：
Licht JD
中科院分区：
文献类型：
--
作者：
Shah MY;Martinez-Garcia E;Phillip JM;Chambliss AB;Popovic R;Ezponda T;Small EC;Will C;Phillip MP;Neri P;Bahlis NJ;Wirtz D;Licht JD
MMSET/WHSC 1是一种在t（4;14）+多发性骨髓瘤（MM）患者中过表达的组蛋白甲基转移酶（HMT），被认为是该MM亚型发病机制的驱动因素。MM中MMSET过表达导致组蛋白3赖氨酸36二甲基化（H3 K36 me 2）增加，组蛋白3赖氨酸27三甲基化（H3 K27 me 3）减少，以及增殖、基因表达和染色质可及性的变化。先前的工作将组蛋白的甲基化与细胞进行DNA损伤修复的能力联系起来。此外，t（4; 14）+患者在包括DNA损伤诱导剂的方案后经常复发，表明MMSET可能在DNA损伤修复和反应中发挥作用。在U2 OS细胞中，我们发现MMSET是有效的非同源末端连接以及同源重组所必需的。MMSET的缺失导致几种DNA修复蛋白表达的缺失，以及DNA修复蛋白向DNA双链断裂（DSB）位点的募集减少。使用具有MMSET的高（病理性）或低（生理性）表达的遗传匹配的MM细胞系，我们发现MMSET高细胞在基线处具有增加的损伤。在添加DNA损伤剂后，MMSET高细胞以增强的速率修复DNA损伤并继续增殖，而MMSET低细胞积累DNA损伤并进入细胞周期停滞。在使用携带诱导型MMSET shRNA的t（4;14）+KMS 11 MM细胞的鼠异种移植模型中，MMSET的消耗增强了化疗的功效，抑制了肿瘤生长并延长了存活期。这些发现有助于解释t（4;14）MM预后较差的原因，并进一步验证MMSET作为MM和其他癌症的潜在治疗靶点。
MMSET/WHSC1 is a histone methyltransferase (HMT) overexpressed in t(4;14)+ multiple myeloma (MM) patients, believed to be the driving factor in the pathogenesis of this MM subtype. MMSET overexpression in MM leads to an increase in histone 3 lysine 36 dimethylation (H3K36me2), and a decrease in histone 3 lysine 27 trimethylation (H3K27me3), as well as changes in proliferation, gene expression, and chromatin accessibility. Prior work linked methylation of histones to the ability of cells to undergo DNA damage repair. In addition, t(4;14)+ patients frequently relapse after regimens that include DNA damage-inducing agents, suggesting that MMSET may play a role in DNA damage repair and response. In U2OS cells, we found that MMSET is required for efficient non-homologous end joining as well as homologous recombination. Loss of MMSET led to loss of expression of several DNA repair proteins, as well as decreased recruitment of DNA repair proteins to sites of DNA double strand breaks (DSBs). Using genetically matched MM cell lines that had either high (pathological) or low (physiological) expression of MMSET, we found that MMSET high cells had increased damage at baseline. Upon addition of a DNA damaging agent, MMSET high cells repaired DNA damage at an enhanced rate and continued to proliferate, whereas MMSET low cells accumulated DNA damage and entered cell cycle arrest. In a murine xenograft model using t(4;14)+ KMS11 MM cells harboring an inducible MMSET shRNA, depletion of MMSET enhanced the efficacy of chemotherapy, inhibiting tumor growth and extending survival. These findings help explain the poorer prognosis of t(4;14) MM and further validate MMSET as a potential therapeutic target in MM and other cancers.
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影响因子：
7.7
作者：
Carvalho S;Vítor AC;Sridhara SC;Martins FB;Raposo AC;Desterro JM;Ferreira J;de Almeida SF
通讯作者：
de Almeida SF
影响因子：
51.1
作者：
Cook, Gordon;Williams, Cathy;Morris, Treen C. M.
通讯作者：
Morris, Treen C. M.
影响因子：
8
作者：
Ezponda, T.;Popovic, R.;Shah, M. Y.;Martinez-Garcia, E.;Zheng, Y.;Min, D-J;Will, C.;Neri, A.;Kelleher, N. L.;Yu, J.;Licht, J. D.
通讯作者：
Licht, J. D.
影响因子：
16.8
作者：
Aymard F;Bugler B;Schmidt CK;Guillou E;Caron P;Briois S;Iacovoni JS;Daburon V;Miller KM;Jackson SP;Legube G
通讯作者：
Legube G
影响因子：
11.2
作者：
Hudlebusch, Heidi Rye;Skotte, Julie;Helin, Kristian
通讯作者：
Helin, Kristian