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

Pan, Di; Yang, Wanwan; Zeng, Yao; Qin, Hongkun; Xu, Yuting; Gui, Yanping; Fan, Xiangshan; Tian, Geng; Wu, Yujia; Sun, Haopeng; Ye, Yuting; Yang, Shihe; Zhou, Jieying; Guo, Qinglong; Zhao, Li

doi:10.1038/s41388-022-02379-7

Cited by 17 publications

(12 citation statements)

References 37 publications

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“…HMGA1 plays an important role in the transcription of RBP4 ( Bianconcini et al, 2009 ). Similar to HMGA1, NRF2/MAFG heterodimer promotes the cell proliferation in HCC ( Pan et al, 2022 ). On the other hand, as a target of farnesoid X receptor (FXR), hepatic MAFG overexpression represses bile acid synthesis and metabolism ( de Aguiar Vallim et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Yang

Ye²,

Zhang³

et al. 2023

Front. Genet.

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Background: Hepatocellular carcinoma (HCC) is one of the most common aggressive malignancies with increasing incidence worldwide. The oncogenic roles of transcription factors (TFs) were increasingly recognized in various cancers. This study aimed to develop a predicting signature based on TFs for the prognosis and treatment of HCC.Methods: Differentially expressed TFs were screened from data in the TCGA-LIHC and ICGC-LIRI-JP cohorts. Univariate and multivariate Cox regression analyses were applied to establish a TF-based prognostic signature. The receiver operating characteristic (ROC) curve was used to assess the predictive efficacy of the signature. Subsequently, correlations of the risk model with clinical features and treatment response in HCC were also analyzed. The TF target genes underwent Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, followed by protein-protein-interaction (PPI) analysis.Results: A total of 25 differentially expressed TFs were screened, 16 of which were related to the prognosis of HCC in the TCGA-LIHC cohort. A 2-TF risk signature, comprising high mobility group AT-hook protein 1 (HMGA1) and MAF BZIP transcription factor G (MAFG), was constructed and validated to negatively related to the overall survival (OS) of HCC. The ROC curve showed good predictive efficiencies of the risk score regarding 1-year, 2-year and 3-year OS (mostly AUC >0.60). Additionally, the risk score independently predicted OS for HCC patients both in the training cohort of TCGA-LIHC dataset (HR = 2.498, p = 0.007) and in the testing cohort of ICGC-LIRI-JP dataset (HR = 5.411, p < 0.001). The risk score was also positively correlated to progressive characteristics regarding tumor grade, TNM stage and tumor invasion. Patients with a high-risk score were more resistant to transarterial chemoembolization (TACE) treatment and agents of lapatinib and erlotinib, but sensitive to chemotherapeutics. Further enrichment and PPI analyses demonstrated that the 2-TF signature distinguished tumors into 2 clusters with proliferative and metabolic features, with the hub genes belonging to the former cluster.Conclusion: Our study identified a 2-TF prognostic signature that indicated tumor heterogeneity with different clinical features and treatment preference, which help optimal therapeutic strategy and improved survival for HCC patients.

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Section: Discussionmentioning

confidence: 99%

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Yang

Ye²,

Zhang³

et al. 2023

Front. Genet.

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“…High expression of AKR1C3 correlated with poor survival ( Zhou et al, 2021 ). AKR1C3 also inhibited the ubiquitination of PARP1 and thus resulting in HCC cell proliferation and resistance to Cisplatin ( Pan et al, 2022 ). Similarly, AKR1B10 also promoted HCC progression and drug resistance ( Zhang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A novel myeloid cell marker genes related signature can indicate immune infiltration and predict prognosis of hepatocellular carcinoma: Integrated analysis of bulk and single-cell RNA sequencing

Zheng

Zhang

et al. 2023

Front. Mol. Biosci.

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Myeloid cells are physiologically related to innate immunity and inflammation. Tumor-associated myeloid cells gained increasing interest because of their critical roles in tumor progression and anticancer immune responses in human malignancies. However, the associations between tumor-associated myeloid cell-related genes and hepatocellular carcinoma have yet to be revealed. Here, through the integrating analysis of bulk and single-cell RNA (scRNA) sequencing of public HCC samples, we developed a gene signature to investigate the role of HCC-specific myeloid signature genes in HCC patients. We firstly defined 317 myeloid cell marker genes through analyzing scRNA data of HCC from the GEO dataset. After selecting the differentially expressed genes, eleven genes were also proved prognostic. Then we built a gene signature from the TCGA cohort and verified further with the ICGC dataset by applying the LASSO Cox method. An eight genes signature (FABP5, C15orf48, PABPC1, TUBA1B, AKR1C3, NQO1, AKR1B10, SPP1) was achieved finally. Patients in the high risk group correlated with higher tumor stages and poor survival than those in the low-risk group. The risk score was proved to be an independent risk factor for prognosis. The high risk group had higher infiltrations of dendritic cells, macrophages and Tregs. And the APC co-inhibition, T cell co-inhibition pathways were also activated. Besides, the risk score positively correlated with multidrug resistance proteins. In conclusion, our myeloid cell marker genes related signature can predict patients’ survival and may also indicate the levels of immune infiltration and drug resistance.

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“…Of note, it has been shown that sorafenib can increase Nrf2 activation in HCC cells 39 . Furthermore, AKR1C3 has been reported to be one of the downstream targets of Nrf2 40 . Therefore, it could be speculated that sustained Nrf2 activation may contribute to the elevation of AKR1C3 in sorafenib-resistant HCC tumor cells.…”

Section: Discussionmentioning

confidence: 99%

AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy

Wu¹,

Dai²,

Li³

et al. 2022

Theranostics

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Rationale: Increased lipid droplet (LD) formation has been linked to tumor metastasis, stemness, and chemoresistance in various types of cancer. Here, we revealed that LD formation is critical for the adaptation to sorafenib in hepatocellular carcinoma (HCC) cells. We aim to investigate the LD function and its regulatory mechanisms in HCC. Methods:The key proteins responsible for LD formation were screened by both metabolomics and proteomics in sorafenib-resistant HCC cells and further validated by immunoblotting and immunofluorescence staining. Biological function of AKR1C3 was evaluated by CRISPR/Cas9-based gene editing. Isotopic tracing analysis with deuterium 3 -labeled palmitate or carbon13-labeled glucose was conducted to investigate fatty acid (FA) and glucose carbon flux. Seahorse analysis was performed to assess the glycolytic flux and mitochondrial function. Selective AKR1C3 inhibitors were used to evaluate the effect of AKR1C3 inhibition on HCC tumor growth and induction of autophagy. Results: We found that long-term sorafenib treatment impairs fatty acid oxidation (FAO), leading to LD accumulation in HCC cells. Using multi-omics analysis in cultured HCC cells, we identified that aldo-keto reductase AKR1C3 is responsible for LD accumulation in HCC. Genetic loss of AKR1C3 fully depletes LD contents, navigating FA flux to phospholipids, sphingolipids, and mitochondria. Furthermore, we found that AKR1C3-dependent LD accumulation is required for mitigating sorafenib-induced mitochondrial lipotoxicity and dysfunction. Pharmacologic inhibition of AKR1C3 activity instantly induces autophagy-dependent LD catabolism, resulting in mitochondrial fission and apoptosis in sorafenib-resistant HCC clones. Notably, manipulation of AKR1C3 expression is sufficient to drive the metabolic switch between FAO and glycolysis. Conclusions: Our findings revealed that AKR1C3-dependent LD formation is critical for the adaptation to sorafenib in HCC through regulating lipid and energy homeostasis. AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.

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

Cited by 17 publications

References 37 publications

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

A novel myeloid cell marker genes related signature can indicate immune infiltration and predict prognosis of hepatocellular carcinoma: Integrated analysis of bulk and single-cell RNA sequencing

AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy

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