Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage.
Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage.
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DOI：
10.1073/pnas.2008772118
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发表时间：
2021-03-30
影响因子：
11.1
通讯作者：
Costello JF
中科院分区：
文献类型：
--
作者：
Amen AM;Fellmann C;Soczek KM;Ren SM;Lew RJ;Knott GJ;Park JE;McKinney AM;Mancini A;Doudna JA;Costello JF
胶质母细胞瘤是一种高致死率的脑癌，目前尚无有效改善患者预后的治疗方案。一项关键的治疗挑战是确定在不影响正常细胞的情况下减少肿瘤负担的方法。我们发现，TERT启动子突变在胶质母细胞瘤中很常见，通过增加gabpb1l -异构体转录因子复合物的结合，导致TERT再激活。反过来，我们发现通过GABPB1L减少对TERT的癌细胞特异性抑制导致近期的抗生长作用和受损的DNA损伤反应，从而大大增加胶质母细胞瘤肿瘤对一线化疗的敏感性。因此，我们的研究结果为GABPB1L抑制联合替莫唑胺化疗作为胶质母细胞瘤的一种有希望的治疗策略提供了理论依据。大多数胶质母细胞瘤（GBMs）通过获得端粒酶逆转录酶（TERT）启动子的突变来实现细胞不朽。TERT启动子突变为GA结合蛋白（GABP）转录因子复合物创造了一个结合位点，GABP转录因子复合物在启动子上的组装与TERT再激活和端粒维持有关。在这里，我们证明了特定的gabpb1l -异构体复合物与突变TERT启动子的结合增加。此外，我们发现TERT启动子突变的GBM细胞与野生型细胞不同，在增殖方面表现出关键的短期依赖GABPB1L，特别是在体内肿瘤建立后。正常情况下，GABPB2蛋白的表达水平很低，而上调GABPB2蛋白可以缓解这种依赖性。更重要的是，当与一线替莫唑胺（TMZ）化疗联合使用时，诱导的GABPB1L下调和相关的TERT减少导致DNA损伤反应受损，导致颅内GBM肿瘤生长显著降低。总之，这些发现提供了对癌症特异性TERT调控机制的见解，揭示了GABPB1L介导的TERT抑制在GBM维持中的快速作用，并建立了GABPB1L抑制联合化疗作为TERT启动子突变型GBM的治疗策略。
Glioblastoma is a highly lethal form of brain cancer with no current treatment options that substantially improve patient outcomes. A key therapeutic challenge is the identification of methods that reduce tumor burden while leaving normal cells unaffected. We show that TERT-promoter mutations, common in glioblastoma, lead to TERT reactivation through increased binding of GABPB1L-isoform–containing transcription factor complexes. In turn, we find that cancer-cell–specific inhibition of TERT through GABPB1L reduction results in near-term anti-growth effects and an impaired DNA damage response that profoundly increase the sensitivity of glioblastoma tumors to frontline chemotherapy. Our results thus provide rationale for GABPB1L inhibition combined with temozolomide chemotherapy treatment as a promising therapeutic strategy for glioblastoma. Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with TERT reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform–containing complex to the mutant TERT promoter. Furthermore, we find that TERT promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated TERT reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific TERT regulation, uncover rapid effects of GABPB1L-mediated TERT suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for TERT promoter mutant GBM.
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影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
影响因子：
4.8
作者：
Chinenov, Y;Henzl, M;Martin, ME
通讯作者：
Martin, ME
DOI：
10.1038/nrd.2016.238
发表时间：
2017-02
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Fellmann C;Gowen BG;Lin PC;Doudna JA;Corn JE
通讯作者：
Corn JE
影响因子：
5.3
作者：
Fragkos, Michalis;Jurvansuu, Jaana;Beard, Peter
通讯作者：
Beard, Peter
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B