Koh Cheryl M, Khattar Ekta, Leow Shi Chi, Liu Chia Yi, Muller Julius, Ang Wei Xia, Li Yinghui, Franzoso Guido, Li Shang, Guccione Ernesto, Tergaonkar Vinay
J Clin Invest. 2015 May;125(5):2109-22. doi: 10.1172/JCI79134. Epub 2015 Apr 20.
Constitutively active MYC and reactivated telomerase often coexist in cancers. While reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with cofactors, confers several growth advantages to cancer cells. It is known that the reactivation of TERT, the catalytic subunit of telomerase, is limiting for reconstituting telomerase activity in tumors. However, while reactivation of TERT has been functionally linked to the acquisition of several "hallmarks of cancer" in tumors, the molecular mechanisms by which this occurs and whether these mechanisms are distinct from the role of telomerase on telomeres is not clear. Here, we demonstrated that first-generation TERT-null mice, unlike Terc-null mice, show delayed onset of MYC-induced lymphomagenesis. We further determined that TERT is a regulator of MYC stability in cancer. TERT stabilized MYC levels on chromatin, contributing to either activation or repression of its target genes. TERT regulated MYC ubiquitination and proteasomal degradation, and this effect of TERT was independent of its reverse transcriptase activity and role in telomere elongation. Based on these data, we conclude that reactivation of TERT, a direct transcriptional MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis.
组成型激活的MYC与重新激活的端粒酶在癌症中常常共存。虽然端粒酶的重新激活被认为是复制永生所必需的，但MYC与辅因子共同作用，赋予癌细胞多种生长优势。已知端粒酶的催化亚基TERT的重新激活是肿瘤中端粒酶活性重建的限制因素。然而，虽然TERT的重新激活在功能上与肿瘤中几种“癌症特征”的获得相关，但这种情况发生的分子机制以及这些机制是否与端粒酶在端粒上的作用不同尚不清楚。在此，我们证明，与Terc基因敲除小鼠不同，第一代TERT基因敲除小鼠显示MYC诱导的淋巴瘤发生延迟。我们进一步确定TERT是癌症中MYC稳定性的调节因子。TERT稳定了染色质上的MYC水平，有助于其靶基因的激活或抑制。TERT调节MYC的泛素化和蛋白酶体降解，并且TERT的这种作用与其逆转录酶活性和在端粒延长中的作用无关。基于这些数据，我们得出结论，肿瘤中直接受MYC转录调控的TERT的重新激活提供了一种前馈机制，以增强MYC依赖性肿瘤发生。
