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SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-27 , DOI: 10.1038/s41419-020-2266-x
Patricia González-Rodríguez 1 , Pinelopi Engskog-Vlachos 1 , Hanzhao Zhang 1, 2 , Adriana-Natalia Murgoci 1 , Ioannis Zerdes 3 , Bertrand Joseph 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-27 , DOI: 10.1038/s41419-020-2266-x
Patricia González-Rodríguez 1 , Pinelopi Engskog-Vlachos 1 , Hanzhao Zhang 1, 2 , Adriana-Natalia Murgoci 1 , Ioannis Zerdes 3 , Bertrand Joseph 1
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Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12-containing complex, distinct from the ATG5-ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12-dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.
中文翻译：
肾透明细胞癌中的SETD2突变可通过调节ATG12抑制自噬。
SETD2基因的失活突变编码非冗余组蛋白H3甲基转移酶和转录调节因子，是透明细胞肾细胞癌（ccRCC）的常见分子特征。SETD2缺乏与ccRCC复发有关，预后价值低。靶向自噬是一种保守的分解代谢过程，在维持细胞稳态和应激条件下的细胞保护中具有关键功能，它正在成为对抗ccRCC的潜在治疗策略。基于表观遗传学的途径现在被认为是自噬调节的关键组成部分。但是，ccRCC细胞中发生的SETD2组蛋白修饰酶功能丧失是否会影响其自噬能力尚待探讨。这里，我们报道RCC细胞中的SETD2缺乏与游离ATG12和另外一个含有ATG12的复合物的异常积累有关，这与ATG5-ATG12复合物不同。在RCC细胞中SETD2缺乏症中SETD2功能的抢救，或该酶在野生型RCC细胞中SETD2表达水平的降低，证明RCC中SETD2缺乏症直接参与自噬过程中这些改变的获得。此外，我们揭示了SETD2的缺陷，已知的替代剪接调节因子，依赖于RCC细胞中规范的长ATG12异构体的短ATG12剪接异构体的表达增加。发现依赖ATG12的共轭系统中的缺陷与自噬通量的降低有关，与这种遍在蛋白样蛋白偶联系统在自噬体形成和扩增中的作用一致。最后，我们报道ccRCC患者的SETD2和ATG12基因表达水平分别与预后良好相关。总体而言，当治疗性干预措施（例如靶向自噬过程）被认为可抗击这些肾癌时，我们的发现为考虑ccRCC肿瘤的SETD2基因状态提出了进一步的论据。
更新日期：2020-01-27
中文翻译：
肾透明细胞癌中的SETD2突变可通过调节ATG12抑制自噬。
SETD2基因的失活突变编码非冗余组蛋白H3甲基转移酶和转录调节因子，是透明细胞肾细胞癌（ccRCC）的常见分子特征。SETD2缺乏与ccRCC复发有关，预后价值低。靶向自噬是一种保守的分解代谢过程，在维持细胞稳态和应激条件下的细胞保护中具有关键功能，它正在成为对抗ccRCC的潜在治疗策略。基于表观遗传学的途径现在被认为是自噬调节的关键组成部分。但是，ccRCC细胞中发生的SETD2组蛋白修饰酶功能丧失是否会影响其自噬能力尚待探讨。这里，我们报道RCC细胞中的SETD2缺乏与游离ATG12和另外一个含有ATG12的复合物的异常积累有关，这与ATG5-ATG12复合物不同。在RCC细胞中SETD2缺乏症中SETD2功能的抢救，或该酶在野生型RCC细胞中SETD2表达水平的降低，证明RCC中SETD2缺乏症直接参与自噬过程中这些改变的获得。此外，我们揭示了SETD2的缺陷，已知的替代剪接调节因子，依赖于RCC细胞中规范的长ATG12异构体的短ATG12剪接异构体的表达增加。发现依赖ATG12的共轭系统中的缺陷与自噬通量的降低有关，与这种遍在蛋白样蛋白偶联系统在自噬体形成和扩增中的作用一致。最后，我们报道ccRCC患者的SETD2和ATG12基因表达水平分别与预后良好相关。总体而言，当治疗性干预措施（例如靶向自噬过程）被认为可抗击这些肾癌时，我们的发现为考虑ccRCC肿瘤的SETD2基因状态提出了进一步的论据。
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