Cellular senescence is characterized by a prolonged and predominantly irreversible cell-cycle arrest state, which is linked to loss of tissue function and aging in mammals. Moreover, in response to aberrant oncogenic signals such as those from oncogenic RAS or BRAF, senescence functions as an intrinsic tumor suppressor mechanism restraining tumor progression. In addition to this durable proliferative block, senescent cells adopt altered morphologies, transcriptional profiles, and metabolism, while often possessing unusual heterochromatin formation termed senescence-associated heterochromatic foci. To uncover genes that are required to permit proliferation in the face of sustained oncogene signaling, we conducted an shRNA-based genetic screen in primary cells expressing inducible BRAF. Here we show that depletion of a known glycolysis regulator, islet amylin polypeptide (IAPP also known as amylin), prevents RAS and BRAF oncogene-induced senescence (OIS) in human cells. Importantly, depletion of IAPP resulted in changes of the cells' metabolome and this metabolic reprogramming was associated with widespread alterations in chromatin modifications compared with senescent cells. Conversely, exogenous treatment of IAPP-depleted cells with amylin restored OIS. Together, our results demonstrate that the metabolic regulator IAPP is important regulator of OIS. Moreover, they suggest that IAPP analog treatment or activation of IAPP signaling in RAS/BRAF mutant tumors may have therapeutic potential through senescence induction. Implications: These findings demonstrate that IAPP is a novel metabolic regulator of oncogene-induced senescence and use of IAPP analogs may be therapeutically effective to restore growth arrest to BRAF and/or RAS mutant cancers. This article is featured in Highlights of This Issue, [p. 741][1] [1]: /lookup/volpage/19/741?iss=5

中文翻译：

---

BRAF 和 RAS 致癌基因诱导的衰老需要代谢调节剂 IAPP（胰淀素）

细胞衰老的特征是长时间且主要是不可逆的细胞周期停滞状态，这与哺乳动物的组织功能丧失和衰老有关。此外，为了响应异常致癌信号，例如来自致癌 RAS 或 BRAF 的信号，衰老作为抑制肿瘤进展的内在肿瘤抑制机制发挥作用。除了这种持久的增殖阻滞，衰老细胞采用改变的形态、转录谱和新陈代谢，同时通常具有不寻常的异染色质形成，称为衰老相关的异染色质病灶。为了揭示在面对持续的癌基因信号传导时允许增殖所需的基因，我们在表达诱导型 BRAF 的原代细胞中进行了基于 shRNA 的遗传筛选。在这里，我们展示了已知糖酵解调节剂的消耗，胰岛糊精多肽（IAPP 也称为糊精）可防止人类细胞中的 RAS 和 BRAF 致癌基因诱导的衰老 (OIS)。重要的是，IAPP 的消耗导致细胞代谢组的变化，并且与衰老细胞相比，这种代谢重编程与染色质修饰的广泛改变有关。相反，用胰淀素对 IAPP 耗尽的细胞进行外源处理可恢复 OIS。总之，我们的结果表明代谢调节剂 IAPP 是 OIS 的重要调节剂。此外，他们认为 IAPP 类似物治疗或激活 RAS/BRAF 突变肿瘤中的 IAPP 信号传导可能通过衰老诱导具有治疗潜力。影响：这些发现表明，IAPP 是一种新的致癌基因诱导衰老的代谢调节剂，使用 IAPP 类似物可能在治疗上有效恢复 BRAF 和/或 RAS 突变癌症的生长停滞。这篇文章被收录在本期的亮点中，[p. 741][1][1]：/lookup/volpage/19/741?iss=5