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.
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The data used and analyzed during the current study are available from the corresponding author on reasonable request.
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This work was supported by grants from the National Natural Science Foundation of China (grants 81872111 and 81672562), National Key Technology R&D Program of China (2019YFC1005200 and 2019YFC1005201), Shanghai Municipal Science and Technology Committee of Shanghai outstanding academic leaders plan (19XD1423100), the project of Outstanding Medical Doctor for Z.Z., Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20181714). We thank all members in Z.Z. lab.
The authors declare no competing interests.
Ethics approval and consent to participate
Human endometrial hyperplasia and cancer tissue samples were obtained from Shanghai General Hospital Affiliated to Shanghai Jiao Tong University and Shanghai First Maternity and Infant Hospital Affiliated to Tongji University School of Medicine. Patients’ informed consent was obtained. All animal studies were approved by the Animal Ethics Committee of Shanghai General Hospital experimental protocols.
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Hu, M., Sun, D., Yu, J. et al. Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00816-5