Nuclear Organization and Oncogenesis Unit, INSERM U993, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, 75015, Paris, France.
Collège Doctoral, Sorbonne Université, 75005, Paris, France.
Oncogene. 2020 Oct;39(43):6692-6703. doi: 10.1038/s41388-020-01457-y. Epub 2020 Sep 18.
Sumoylation is an essential posttranslational modification in eukaryotes that has emerged as an important pathway in oncogenic processes. Most human cancers display hyperactivated sumoylation and many cancer cells are remarkably sensitive to its inhibition, thus supporting application of chemical sumoylation inhibitors in cancer treatment. Here we show, first, that transformed embryonic fibroblasts derived from mice haploinsufficient for Ubc9, the essential and unique gene encoding the SUMO E2 conjugating enzyme, exhibit enhanced proliferation and transformed phenotypes in vitro and as xenografts ex vivo. To then evaluate the possible impact of loss of one Ubc9 allele in vivo, we used a mouse model of intestinal tumorigenesis. We crossed Ubc9 mice with mice harboring a conditional ablation of Apc either all along the crypt-villus axis or only in Lgr5 crypt-based columnar (CBC) cells, the cell compartment that includes the intestinal stem cells proposed as cells-of-origin of intestinal cancer. While Ubc9 mice display no overt phenotypes and no globally visible hyposumoylation in cells of the small intestine, we found, strikingly, that, upon loss of Apc in both models, Ubc9 mice develop more (>2-fold) intestinal adenomas and show significantly shortened survival. This is accompanied by reduced global sumoylation levels in the polyps, indicating that Ubc9 levels become critical upon oncogenic stress. Moreover, we found that, in normal conditions, Ubc9 mice show a moderate but robust (15%) increase in the number of Lgr5 CBC cells when compared to their wild-type littermates, and further, that these cells display higher degree of stemness and cancer-related and inflammatory gene expression signatures that, altogether, may contribute to enhanced intestinal tumorigenesis. The phenotypes of Ubc9 haploinsufficiency discovered here indicate an unanticipated tumor-suppressive role of sumoylation, one that may have important implications for optimal use of sumoylation inhibitors in the clinic.
泛素化是真核生物中一种重要的翻译后修饰，已成为致癌过程中的重要途径。大多数人类癌症表现出过度激活的泛素化，许多癌细胞对其抑制非常敏感，因此支持在癌症治疗中应用化学泛素化抑制剂。在这里，我们首先表明，来自 Ubc9 杂合缺失的小鼠的转化胚胎成纤维细胞，Ubc9 是编码 SUMO E2 连接酶的必需和独特基因，在体外和作为异种移植物表现出增强的增殖和转化表型。为了评估体内失去一个 Ubc9 等位基因的可能影响，我们使用了一种肠道肿瘤发生的小鼠模型。我们将 Ubc9 小鼠与在整个隐窝-绒毛轴或仅在 Lgr5 隐窝基柱状（CBC）细胞中条件性缺失 Apc 的小鼠进行杂交，CBC 细胞包括被提议为肠道癌起源细胞的肠道干细胞。虽然 Ubc9 小鼠没有明显的表型，并且在小肠细胞中没有明显的低泛素化，但我们发现，令人惊讶的是，在两种模型中丢失 Apc 后，Ubc9 小鼠发展出更多 (>2 倍) 的肠道腺瘤，并且存活率显著缩短。这伴随着息肉中整体泛素化水平的降低，表明 Ubc9 水平在致癌应激下变得至关重要。此外，我们发现，在正常情况下，与野生型同窝仔相比，Ubc9 小鼠的 Lgr5 CBC 细胞数量增加了 15%，而且这些细胞表现出更高的干性和与癌症相关的和炎症基因表达特征，这些特征加在一起可能有助于增强肠道肿瘤发生。这里发现的 Ubc9 杂合不足的表型表明泛素化具有出乎意料的肿瘤抑制作用，这可能对临床中泛素化抑制剂的最佳应用具有重要意义。
