Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Department of Surgery and Cancer, Imperial College London, London, UK.
EMBO Rep. 2021 Mar 3;22(3):e50852. doi: 10.15252/embr.202050852. Epub 2021 Feb 15.
Transition from proliferative-to-invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down-regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR-depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re-expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor-initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient-rich conditions by repressing translation of selected ISR RNAs.
从增生表型向侵袭表型的转变促进了黑色素瘤的转移和治疗耐药性。然而，由于对维持侵袭表型的机制缺乏了解，侵袭表型的逆转受到了挑战。在这里，我们报告 TINCR 在转移性黑色素瘤中表达下调，其沉默会增加侵袭性标志物的表达水平，体外迁移，体内肿瘤生长以及对 BRAF 和 MEK 抑制剂的耐药性。关键的介质是 ATF4，它是整合应激反应（ISR）的核心参与者，在 TINCR 耗尽的细胞中，即使在没有饥饿和 eIF2α 磷酸化的情况下，它也会被激活。TINCR 耗尽会增加整体蛋白质合成并诱导翻译重编程，从而导致编码 ATF4 和其他 ISR 蛋白的 mRNA 翻译增加。引人注目的是，在转移性黑色素瘤中重新表达 TINCR 会抑制侵袭表型，减少肿瘤起始细胞和转移形成的数量，并增加药物敏感性。从机制上讲，TINCR 与与侵袭表型相关的 mRNA 相互作用，包括 ATF4，从而阻止它们与核糖体结合。因此，TINCR 是黑色素瘤侵袭表型的抑制剂，它在营养丰富的条件下通过抑制选定的 ISR RNA 的翻译起作用。
