THOR is a targetable epigenetic biomarker with clinical implications in breast cancer.
THOR is a targetable epigenetic biomarker with clinical implications in breast cancer.
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DOI：
10.1186/s13148-022-01396-3
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发表时间：
2022-12-18
影响因子：
5.7
通讯作者：
Castelo-Branco, Pedro
中科院分区：
文献类型：
--
作者：
Apolonio, Joana Dias;Dias, Joao S.;Fernandes, Monica Teotonio;Komosa, Martin;Lipman, Tatiana;Zhang, Cindy H.;Leao, Ricardo;Lee, Donghyun;Nunes, Nuno Miguel;Maia, Ana-Teresa;Morera, Jose L.;Vicioso, Luis;Tabori, Uri;Castelo-Branco, Pedro
乳腺癌 (BC) 是最常诊断的癌症，也是全球女性死亡的主要原因。早期 BC 是有可能治愈的，但 BC 患者中仍然观察到的死亡率表明迫切需要新颖且更有效的诊断和治疗方案。无限的自我更新是癌症的一个标志，由端粒维持控制。在大约 95% 的 BC 病例中，这一过程是通过上调人类端粒酶逆转录酶 (hTERT) 来重新激活端粒酶来实现的。 hTERT 启动子内特定区域的高甲基化，称为 TERT 高甲基化肿瘤区域 (THOR)，与癌症中 hTERT 表达增加相关。然而，据我们所知，其在 BC 中的生物学作用和临床潜力从未被研究过。因此，我们的目的是研究 THOR 作为生物标志物的作用，并探讨 THOR 甲基化状态对 BC 中 hTERT 上调的功能影响。通过对发现和验证队列进行焦磷酸测序来评估 BC 中的 THOR 甲基化状态。我们发现，与良性组织相比，恶性乳腺组织中的THOR显着高甲基化（40.23% vs. 12.81%，P<0.0001），从疾病的最早阶段就将恶性肿瘤与正常组织区分开来。使用报告基因检测，与单独的 hTERT 核心启动子相比，添加未甲基化的 THOR 显着降低了荧光素酶活性，平均降低了 1.8 倍（P < 0.01）。为了进一步研究其对hTERT转录的生物学影响，利用基于CRISPR-dCas9系统的新技术进行了靶向THOR去甲基化，并实现了显着的THOR去甲基化。先前在 THOR 区域去甲基化的细胞在体内测定中并未形成组织学癌症表型。需要进行更多研究来验证这些观察结果，并揭示 BC 中 THOR 高甲基化和 hTERT 上调之间的因果关系。 THOR 高甲基化是乳腺肿瘤发生中重要的表观遗传标记，代表了 BC 中一个有前途的生物标志物和治疗靶点。我们发现 THOR 作为 hTERT 的抑制性调节元件，其高甲基化是 BC 中 hTERT 上调的相关机制。在线版本包含可在 10.1186/s13148-022-01396-3 获取的补充材料。
Breast cancer (BC) is the most frequently diagnosed cancer and a leading cause of death among women worldwide. Early BC is potentially curable, but the mortality rates still observed among BC patients demonstrate the urgent need of novel and more effective diagnostic and therapeutic options. Limitless self-renewal is a hallmark of cancer, governed by telomere maintenance. In around 95% of BC cases, this process is achieved by telomerase reactivation through upregulation of the human telomerase reverse transcriptase (hTERT). The hypermethylation of a specific region within the hTERT promoter, termed TERT hypermethylated oncological region (THOR) has been associated with increased hTERT expression in cancer. However, its biological role and clinical potential in BC have never been studied to the best of our knowledge. Therefore, we aimed to investigate the role of THOR as a biomarker and explore the functional impact of THOR methylation status in hTERT upregulation in BC. THOR methylation status in BC was assessed by pyrosequencing on discovery and validation cohorts. We found that THOR is significantly hypermethylated in malignant breast tissue when compared to benign tissue (40.23% vs. 12.81%, P < 0.0001), differentiating malignant tumor from normal tissue from the earliest stage of disease. Using a reporter assay, the addition of unmethylated THOR significantly reduced luciferase activity by an average 1.8-fold when compared to the hTERT core promoter alone (P < 0.01). To further investigate its biological impact on hTERT transcription, targeted THOR demethylation was performed using novel technology based on CRISPR-dCas9 system and significant THOR demethylation was achieved. Cells previously demethylated on THOR region did not develop a histologic cancer phenotype in in vivo assays. Additional studies are required to validate these observations and to unravel the causality between THOR hypermethylation and hTERT upregulation in BC. THOR hypermethylation is an important epigenetic mark in breast tumorigenesis, representing a promising biomarker and therapeutic target in BC. We revealed that THOR acts as a repressive regulatory element of hTERT and that its hypermethylation is a relevant mechanism for hTERT upregulation in BC. The online version contains supplementary material available at 10.1186/s13148-022-01396-3.
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影响因子：
--
作者：
Gay-Bellile M;Véronèse L;Combes P;Eymard-Pierre E;Kwiatkowski F;Dauplat MM;Cayre A;Privat M;Abrial C;Bignon YJ;Mouret-Reynier MA;Vago P;Penault-Llorca F;Tchirkov A
通讯作者：
Tchirkov A
影响因子：
6.2
作者：
Huang, F. W.;Bielski, C. M.;Kryukov, G. V.
通讯作者：
Kryukov, G. V.
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F
影响因子：
3.5
作者：
Gaspar TB;Sá A;Lopes JM;Sobrinho-Simões M;Soares P;Vinagre J
通讯作者：
Vinagre J
DOI：
10.1016/j.bbrc.2004.10.137
发表时间：
2004-12-17
影响因子：
3.1
作者：
Guilleret, I;Benhattar, J
通讯作者：
Benhattar, J