Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
Department of Obstetrics and Gynecology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China.
Lab Invest. 2022 Dec;102(12):1335-1345. doi: 10.1038/s41374-022-00816-5. Epub 2022 Aug 29.
Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.
孕激素抵抗是子宫内膜癌患者采用保守疗法维持生育能力的主要障碍。布瑞沙托醇被鉴定为 NRF2 通路的抑制剂；然而，其对孕激素抵抗的影响及其潜在机制尚不清楚。在这里，我们发现布瑞沙托醇通过抑制 NRF2-TET1-AKR1C1 介导的孕激素代谢来使子宫内膜癌对孕激素敏感。布瑞沙托醇通过抑制 TET1 来修饰其启动子区域的羟甲基化状态，从而转录抑制 AKR1C1。布瑞沙托醇抑制 AKR1C1 导致孕激素代谢减少，并保持孕激素的强烈抑制作用以抑制子宫内膜癌生长。这种抑制模式也在已建立的异种移植小鼠和类器官模型中得到发现。在孕激素抵抗的同一患者的配对子宫内膜增生和癌症样本中发现 AKR1C1 异常过表达，而与配对的预处理组织相比，在孕激素反应良好的治疗后样本中观察到 AKR1C1 减弱或缺失。我们的研究结果表明，AKR1C1 的表达模式可能是子宫内膜癌孕激素抵抗的一个重要生物标志物。
