Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy.
Departament de Biologia Cel.lular, Fisiologia i Immunologia, Facultad de Biologia, Universitat de Barcelona (UB), 08028, Barcelona, Spain.
Nat Commun. 2022 Mar 21;13(1):1503. doi: 10.1038/s41467-022-29085-y.
Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APC mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.
尽管细胞代谢的重新编程是癌症的一个标志，但对于代谢重编程如何促进转化的早期阶段知之甚少。在这里，我们表明组蛋白去乙酰化酶 SIRT6 通过控制葡萄糖代谢来调节肠道癌症中的肿瘤起始。SIRT6 的缺失导致肠干细胞 (ISC) 的数量增加，这转化为 APC 小鼠中增强的肿瘤起始潜力。通过追踪葡萄糖代谢与肿瘤起始之间的联系，我们在肠道上皮细胞和腺瘤中发现了一个代谢分隔区，其中一小部分细胞表现出类似于沃伯格代谢的特征，其特点是丙酮酸脱氢酶激酶 (PDK) 活性高。我们的结果表明，这些细胞是具有 +4 ISC 和肠内分泌标志物的静止细胞。这些细胞中活跃的糖酵解抑制 ROS 积累并增强其干细胞和致瘤潜能。我们的研究表明，有氧糖酵解代表了癌症的一种异质特征，并表明这种代谢适应可以发生在非分裂细胞中，这表明沃伯格效应在肿瘤中的作用不仅仅是生物量的产生。
