Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (array)

Constitutively active MYC and reactivated telomerase often co-exist in cancers. While the reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with co-factors, confers several growth advantages to cancer cells. However, it is unclear which co-factors sustain elevated MYC activity in tumors . Here, we identify TERT, the catalytic subunit of telomerase, as a novel regulator of MYC stability in cancers. Binding of TERT to MYC stabilizes its levels on chromatin, contributing to either activation or repression of its target genes. Mechanistically, TERT regulates MYC ubiquitination and stability, and this effect of TERT is independent of its role on telomeres. Genetic inhibition and knocking out of TERT phenocopied the loss of MYC, resulting in reduced disease burden of early- and late-stage MYC-driven murine lymphomas. Conversly, the ectopic expression of TERT could substitute for reduced MYC in these functions. Finally we show that TERT null mice, unlike Terc null mice, show delayed onset of MYC induced lymphomagenesis. Accordingly, inhibiting TERT function in primary human leukemia cells blocked the expression of MYC targets, while Terc depletion had no effects . Based on our data, we conclude that the re-expression of TERT, a direct MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis. P493 cells were stably infected with the following viruses: pLKO shControl and pLKO shTERT.

组成型激活的MYC与重新激活的端粒酶常在癌症中共存。尽管端粒酶的重新激活被认为是癌细胞获得复制永生能力的必要条件，但MYC可与其辅因子协同，为癌细胞赋予多重生长优势。然而，目前尚不清楚哪些辅因子可维持肿瘤中MYC的高活性。本研究鉴定出端粒酶催化亚基（TERT）作为癌症中MYC稳定性的新型调控因子。TERT与MYC结合可稳定其在染色质上的表达水平，进而调控MYC靶基因的激活或抑制。从机制上讲，TERT可调控MYC的泛素化与稳定性，且该作用不依赖其在端粒上的功能。通过基因抑制与敲除TERT，可模拟MYC缺失的表型，降低早期及晚期MYC驱动型小鼠淋巴瘤的疾病负荷。反之，在上述细胞中异位表达TERT，可替代MYC表达下调所产生的相关功能。最后，我们证实与端粒酶RNA组分（Terc）敲除小鼠不同，TERT敲除小鼠的MYC诱导淋巴瘤发生进程显著延迟。据此，在原代人白血病细胞中抑制TERT功能可阻断MYC靶基因的表达，而Terc敲除则无此效果。综合上述数据，我们认为作为肿瘤中直接的MYC靶基因，TERT的重新表达可形成前馈调控机制，增强MYC依赖的肿瘤发生过程。本研究中使用的P493细胞已通过以下病毒完成稳定感染：pLKO shControl与pLKO shTERT。