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AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma

Abstract

Aldo-keto reductase family 1 member C3 (AKR1C3) serves as a contributor to numerous kinds of tumors, and its expression is elevated in patients with hepatocellular carcinoma (HCC). However, the biological function of AKR1C3 in HCC remains unclear. Here we investigated the role of AKR1C3 in liver carcinogenesis using in vitro and in vivo models. We determined that AKR1C3 is frequently increased in HCC tissues with poor prognosis. Genetically manipulated cells with AKR1C3 construction were examined to highlight the pro-tumoral growth of both wild-type AKR1C3 and mutant in vitro and in vivo. We observed promising treatment effects of AKR1C3 shRNA by intratumoral injection in mice. Mechanically, we demonstrated that the transcription factor heterodimer NRF2/MAFG was able to bind directly to AKR1C3 promoter to activate its transcription. Further, AKR1C3 stabilized PARP1 by decreasing its ubiquitination, which resulted in HCC cell proliferation and low sensitivity of Cisplatin. Moreover, we discovered that the tumorigenic role of AKR1C3 was non-catalytic dependent and the NRF2/MAFG-AKR1C3-PARP1 axis might be one of the important proliferation pathways in HCC. In conclusion, blockage of AKR1C3 expression provides potential therapeutic benefits against HCC.

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Fig. 1: AKR1C3 is elevated in HCC tissues and associated with multiple clinical features.
Fig. 2: AKR1C3 promotes HCC cells proliferation independent on its enzymatic activity.
Fig. 3: NRF2/MAFG complex transcript AKR1C3 expression.
Fig. 4: AKR1C3 stabilizes PARP1 by reducing its ubiquitination.
Fig. 5: MAFG-AKR1C3-PARP1 axis promotes HCC proliferation.
Fig. 6: Schematic representation of the NRF2/MAFG-AKR1C3-PARP1 axis promoting HCC progression.

References

  1. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

    Article  Google Scholar 

  2. Ricciotti E, Wangensteen KJ, FitzGerald GA. Aspirin in hepatocellular carcinoma. Cancer Res. 2021;81:3751–61.

    CAS  Article  Google Scholar 

  3. Feng M, Pan Y, Kong R, Shu S. Therapy of primary liver cancer. Innovation. 2020;1:100032.

    PubMed  PubMed Central  Google Scholar 

  4. Rižner T, Penning T. Aldo-keto reductase 1C3-assessment as a new target for the treatment of endometriosis. Pharmacol Res. 2020;152:104446.

    Article  Google Scholar 

  5. Kim SY, Shen Q, Son K, Kim HS, Yang HD, Na MJ, et al. SMARCA4 oncogenic potential via IRAK1 enhancer to activate Gankyrin and AKR1B10 in liver cancer. Oncogene. 2021;40:4652–62.

    CAS  Article  Google Scholar 

  6. Penning TM. AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): roles in malignancy and endocrine disorders. Mol Cell Endocrinol. 2019;489:82–91.

    CAS  Article  Google Scholar 

  7. Zeng CM, Chang LL, Ying MD, Cao J, He QJ, Zhu H, et al. Aldo-Keto reductase AKR1C1-AKR1C4: Functions, Regulation, and Intervention for anti-cancer therapy. Front Pharmacol. 2017;8:119.

    Article  Google Scholar 

  8. Penning TM, Wangtrakuldee P, Auchus RJ. Structural and functional biology of aldo-keto reductase steroid-transforming enzymes. Endocr Rev. 2019;40:447–75.

    Article  Google Scholar 

  9. Penning TM. The aldo-keto reductases (AKRs): overview. Chem-Biol Interact. 2015;234:236–46.

    CAS  Article  Google Scholar 

  10. Penning TM. Aldo-Keto reductase (AKR) 1C3 inhibitors: a patent review. Expert Opin Ther Pat. 2017;27:1329–40.

    CAS  Article  Google Scholar 

  11. Powell K, Semaan L, Conley-LaComb MK, Asangani I, Wu YM, Ginsburg KB, et al. ERG/AKR1C3/AR constitutes a feed-forward loop for ar signaling in prostate cancer cells. Clin Cancer Res. 2015;21:2569–79.

    CAS  Article  Google Scholar 

  12. Rheinbay E, Nielsen MM, Abascal F, Wala JA, Shapira O, Tiao G, et al. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature. 2020;578:102–11.

    CAS  Article  Google Scholar 

  13. Zhao S, Wang S, Zhao Z, Li W. AKR1C1-3, notably AKR1C3, are distinct biomarkers for liver cancer diagnosis and prognosis: database mining in malignancies. Oncol Lett. 2019;18:4515–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhou Q, Tian W, Jiang Z, Huang T, Ge C, Liu T. et al. A positive feedback loop of AKR1C3-mediated activation of NF-kappaB and STAT3 facilitates proliferation and metastasis in hepatocellular carcinoma. Cancer Res. 2021;81:1361–1374.

    CAS  Article  Google Scholar 

  15. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:556–60.

    Article  Google Scholar 

  16. Jackson VJ, Yosaatmadja Y, Flanagan JU, Squire CJ. Structure of AKR1C3 with 3-phenoxybenzoic acid bound. Acta Cry Sect F Struct Biol Cry Com. 2012;68:409–13.

    CAS  Article  Google Scholar 

  17. Hu Z, Wang X, Li D, Cao L, Cui H, Xu G. UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2. Oncogene. 2021;40:647–62.

    CAS  Article  Google Scholar 

  18. Bortolozzi R, Bresolin S, Rampazzo E, Paganin M, Maule F, Mariotto E, et al. AKR1C enzymes sustain therapy resistance in paediatric T-ALL. Br J Cancer. 2018;118:985–94.

    CAS  Article  Google Scholar 

  19. Katsuoka F, Yamamoto M. Small Maf proteins (MafF, MafG, MafK): history, structure and function. Gene. 2016;586:197–205.

    CAS  Article  Google Scholar 

  20. Curtin N, Szabo C. Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat Rev Drug Discov. 2020;19:711–36.

    CAS  Article  Google Scholar 

  21. Mantel A, Carpenter-Mendini AB, Vanbuskirk JB, De Benedetto A, Beck LA, Pentland AP. Aldo-keto reductase 1C3 is expressed in differentiated human epidermis, affects keratinocyte differentiation, and is upregulated in atopic dermatitis. J Investig Dermatol. 2012;132:1103–10.

    CAS  Article  Google Scholar 

  22. Liu Y, He S, Chen Y, Liu Y, Feng F, Liu W, et al. Overview of AKR1C3: inhibitor achievements and disease insights. J Med Chem. 2020;63:11305–29.

    CAS  Article  Google Scholar 

  23. Xie L, Yu J, Guo W, Wei L, Liu Y, Wang X, et al. Aldo-keto reductase 1C3 may be a new radioresistance marker in non-small-cell lung cancer. Cancer Gene Ther. 2013;20:260–6.

    CAS  Article  Google Scholar 

  24. Matsunaga T, Okumura N, Saito H, Morikawa Y, Suenami K, Hisamatsu A, et al. Significance of aldo-keto reductase 1C3 and ATP-binding cassette transporter B1 in gain of irinotecan resistance in colon cancer cells. Chem Biol Interact. 2020;332:109295.

    CAS  Article  Google Scholar 

  25. de Aguiar Vallim TQ, Tarling EJ, Ahn H, Hagey LR, Romanoski CE, Lee RG, et al. MAFG is a transcriptional repressor of bile acid synthesis and metabolism. Cell Metab. 2015;21:298–311.

    Article  Google Scholar 

  26. Hirotsu Y, Katsuoka F, Funayama R, Nagashima T, Nishida Y, Nakayama K, et al. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. 2012;40:10228–39.

    CAS  Article  Google Scholar 

  27. Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017;18:610–21.

    CAS  Article  Google Scholar 

  28. Noordermeer S, van Attikum H. PARP inhibitor resistance: a tug-of-war in BRCA-mutated cells. Trends Cell Biol. 2019;29:820–34.

    CAS  Article  Google Scholar 

  29. Ko H, Ren E. Novel poly (ADP-ribose) polymerase 1 binding motif in hepatitis B virus core promoter impairs DNA damage repair. Hepatology. 2011;54:1190–8.

    CAS  Article  Google Scholar 

  30. Dong Q, Du Y, Li H, Liu C, Wei Y, Chen M, et al. EGFR and c-MET cooperate to enhance resistance to PARP inhibitors in hepatocellular carcinoma. Cancer Res. 2019;79:819–29.

    CAS  Article  Google Scholar 

  31. Vera-Puente O, Rodriguez-Antolin C, Salgado-Figueroa A, Michalska P, Pernia O, Reid BM, et al. MAFG is a potential therapeutic target to restore chemosensitivity in cisplatin-resistant cancer cells by increasing reactive oxygen species. Transl Res. 2018;200:1–17.

    CAS  Article  Google Scholar 

  32. Wu T, Wang X, Tian W, Jaramillo M, Lau A, Zhang D. Poly(ADP-ribose) polymerase-1 modulates Nrf2-dependent transcription. Free Radic Biol Med. 2014;67:69–80.

    CAS  Article  Google Scholar 

  33. Velica P, Davies NJ, Rocha PP, Schrewe H, Ride JP, Bunce CM. Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: implications for modelling human cancers. Mol Cancer Ther. 2009;8:121.

    Article  Google Scholar 

  34. Gatti M, Imhof R, Huang Q, Baudis M, Altmeyer M. The ubiquitin ligase TRIP12 limits PARP1 trapping and constrains PARP inhibitor efficiency. Cell Rep. 2020;32:107985.

    CAS  Article  Google Scholar 

  35. Zhang L, Li D. MORC2 regulates DNA damage response through a PARP1-dependent pathway. Nucleic Acids Res. 2019;47:8502–20.

    CAS  Article  Google Scholar 

  36. Cao C, Yang J, Chen Y, Zhou P, Wang Y, Du W, et al. Discovery of SK-575 as a highly potent and efficacious proteolysis-targeting chimera degrader of PARP1 for treating cancers. J Med Chem. 2020;63:11012–33.

    CAS  Article  Google Scholar 

  37. Zhao Q, Lan T, Su S, Rao Y. Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule. Chem Commun. 2019;55:369–72.

    CAS  Article  Google Scholar 

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Acknowledgements

We wish to thank Jia Li, Siyu He and Canping Chen (China Pharmaceutical University) for technical guidance. Also, we wish to thank the help from the following professors of China Pharmaceutical University, Dr. Lei Qiang for gifting plasmids, Dr. Xiaosheng Wang for bioinformation direction and Dr. Zhaoqiu Wu for writing direction. Further, we wish to acknowledge pathologists Hongyan Wu (Nanjing Drum Tower Hospital) and Zhiwen Li (Nanjing Drum Tower Hospital) for the HCC tissue microarray technique and immunoreactive score.

Funding

This work was supported by the Key Program of the National Science Foundation of China (81830105); the program of the National Science Foundation of China (81773774).

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DP, WwY and YZ: conceptualization & methodology; formal analysis; writing-original draft. HkQ and YpG: visualization; data curation; formal analysis. YtX, GT, YjW, ShY and YtY: Investigation; Formal analysis; Resources. XsF: HCC specimen resources; Validation. HpS: Methodology; Conceptualization. JyZ: Writing editing. QlG: project administration; funding acquisition. LZ: conceptualization; supervision; funding acquisition; project administration.

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Correspondence to Qinglong Guo or Li Zhao.

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Pan, D., Yang, W., Zeng, Y. et al. AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma. Oncogene 41, 3846–3858 (2022). https://doi.org/10.1038/s41388-022-02379-7

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