Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers.
Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers.
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DOI：
10.3390/cancers14020357
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发表时间：
2022-01-12
期刊：
影响因子：
5.2
通讯作者：
Landa I
中科院分区：
文献类型：
--
作者：
Thornton CEM;Hao J;Tamarapu PP;Landa I
端粒酶逆转录酶（TERT）基因启动子区的突变在晚期甲状腺肿瘤患者中富集。其结果是通过涉及特定转录因子和其他信号输入的机制重新激活TERT表达。在这里，我们表明，与其他肿瘤类型相反，ETS家族的多种因子能够控制TERT转录，并且在启动子突变存在和不存在的情况下都是如此。我们还发现，在没有TERT启动子突变的甲状腺细胞中，TERT表达更依赖于MAPK信号通路。我们的工作指出了甲状腺肿瘤中一个复杂的、尚未完全表征的TERT转录调节网络。我们警告不要假设在其他癌症谱系中确定的机制在TERT突变的甲状腺标本中是相同的。端粒酶逆转录酶（TERT）基因的热点突变是甲状腺癌进展的关键决定因素。TERT启动子突变（TPM）为转录因子的ETS（“E26转化特异性”）家族产生从头共有结合位点。在这项研究中，我们系统地敲低了甲状腺肿瘤中表达的20个ETS因子中的每一个，并筛选了它们对7个具有确定TPM状态的甲状腺癌细胞系中TERT表达的影响。我们观察到，与其他携带TPM的癌症（如胶质母细胞瘤）不同，ETS因子GABPA并不明确地调节甲状腺标本中TERT突变启动子的转录。事实上，ETS家族的多个成员影响TERT表达，并且它们通常以突变独立的方式这样做。此外，我们观察到，部分抑制MAPK，甲状腺癌转化的中心途径，是更有效地抑制在TPMs的情况下的TERT转录。综上所述，我们的研究结果显示，与其他谱系相比，甲状腺癌中的TERT调控更为复杂，并表明ETS和其他调节剂的补偿机制可能存在，并主张在最终探索TPM特异性治疗策略之前，需要更全面地了解甲状腺肿瘤中的TERT失调机制。
Mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene are enriched in patients with advanced thyroid tumors. Their consequence is the reactivation of TERT expression through mechanisms that involve specific transcription factors and other signaling inputs. Here, we show that, contrary to what it has been shown in other tumor types, multiple factors of the ETS family are able to control TERT transcription and they do so in both the presence and absence of promoter mutations. We also show that TERT expression is more dependent on the MAPK signaling pathway in thyroid cells without TERT promoter mutations. Our work points to an intricate, still not fully characterized, regulatory network of TERT transcription in thyroid tumors. We caution against the assumption of mechanisms identified in other cancer lineages being identical in TERT-mutant thyroid specimens. Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.
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