Khaket Tejinder Pal, Rimal Suman, Wang Xingjun, Bhurtel Sunil, Wu Yen-Chi, Lu Bingwei
Department of Pathology and Programs in Neuroscience and Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
PNAS Nexus. 2024 Aug 13;3(8):pgae321. doi: 10.1093/pnasnexus/pgae321. eCollection 2024 Aug.
Myc is a major driver of tumor initiation, progression, and maintenance. Up-regulation of Myc protein level rather than acquisition of neomorphic properties appears to underlie most Myc-driven cancers. Cellular mechanisms governing Myc expression remain incompletely defined. In this study, we show that ribosome-associated quality control (RQC) plays a critical role in maintaining Myc protein level. Ribosomes stall during the synthesis of the N-terminal portion of cMyc, generating aberrant cMyc species and necessitating deployment of the early RQC factor ZNF598 to handle translational stress and restore translation. ZNF598 expression is up-regulated in human glioblastoma (GBM), and its expression positively correlates with that of cMyc. ZNF598 knockdown inhibits human GBM neurosphere formation in cell culture and Myc-dependent tumor growth in vivo in . Intriguingly, the SARS-COV-2-encoded translational regulator Nsp1 impinges on ZNF598 to restrain cMyc translation and consequently cMyc-dependent cancer growth. Remarkably, Nsp1 exhibits synthetic toxicity with the translation and RQC-related factor ATP-binding cassette subfamily E member 1, which, despite its normally positive correlation with cMyc in cancer cells, is co-opted by Nsp1 to down-regulate cMyc and inhibit tumor growth. Ribosome stalling during translation thus offers actionable cancer cell vulnerability.
Myc是肿瘤起始、进展和维持的主要驱动因素。Myc驱动的大多数癌症似乎是基于Myc蛋白水平的上调，而非获得新的形态特性。调控Myc表达的细胞机制仍未完全明确。在本研究中，我们表明核糖体相关质量控制（RQC）在维持Myc蛋白水平方面发挥关键作用。核糖体在cMyc N端部分的合成过程中停滞，产生异常的cMyc物种，因此需要早期RQC因子ZNF598发挥作用来应对翻译应激并恢复翻译。ZNF598在人类胶质母细胞瘤（GBM）中表达上调，其表达与cMyc呈正相关。敲低ZNF598可抑制细胞培养中人类GBM神经球的形成以及体内Myc依赖性肿瘤的生长。有趣的是，严重急性呼吸综合征冠状病毒2（SARS-COV-2）编码的翻译调节因子Nsp1作用于ZNF598，以抑制cMyc的翻译，从而抑制cMyc依赖性癌症的生长。值得注意的是，Nsp1与翻译及RQC相关因子ATP结合盒亚家族E成员1表现出合成毒性，尽管该因子在癌细胞中通常与cMyc呈正相关，但被Nsp1利用来下调cMyc并抑制肿瘤生长。因此，翻译过程中的核糖体停滞为癌细胞提供了可利用的脆弱性。
