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Hereditary Leiomyomatosis and Renal Cell Cancer: Recent Insights Into Mechanisms and Systemic Treatment - PubMed

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Hereditary Leiomyomatosis and Renal Cell Cancer: Recent Insights Into Mechanisms and Systemic Treatment

Congwang Zhang et al. Front Oncol. 2021.

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant hereditary cancer syndrome characterized by a predisposition to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). It is known to be caused by germline mutations of the fumarate hydratase (FH) gene, which encodes an enzyme component of the citric acid cycle and catalyzes the conversion of fumarate to L-malate. Currently, there is no standardized treatment for HLRCC, which may be due in part to a lack of understanding of the underlying mechanisms. Here, the underlying molecular mechanisms by which the inactivation of FH causes HLRCC are discussed. Additionally, potential therapeutic pharmacological strategies are also summarized to provide new perspectives for the prevention and treatment of HLRCC.

Keywords: fumarate hydratase; hereditary leiomyomatosis and renal cell carcinoma; mechanism; pathogenesis; treatment.

Copyright © 2021 Zhang, Li, Zhang and Zeng.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1

Schematic representation of HLRCC pathway. HLRCC, marked by defective oxidative phosphorylation, undergoes a metabolic transition to aerobic glycolysis to produce ATP required for the energetic requirements of proliferating cells. Enhanced glycolysis represses AMPK expression and activation, resulting in increased S6 and ACC activity, fostering anabolic growth and proliferation. Decreased AMPK yields decreased p53 and iron transporter DMT1. Cytosolic iron concentrations will suppress prolyl hydroxylase, which is susceptible to iron levels, stabilizing HIF1α. Fumarate, which rises in FH-deficient cells, has been shown to suppress prolyl hydroxylase, which will contribute to more stabilization of HIF1α, enhancing the transcription of factors such as VEGF and GLUT1. Enhanced fumarate was shown to succinate KEAP1, thereby altering its conformation and affecting its capacity to cause Nrf2 degradation. Nrf2 transcription activates anti-oxidant reactions and protects against oxidative stress. Increased HIF1α will stimulate LDHA, increase lactate development, and stimulate PDK1, which inhibits PHD and decreases pyruvate entry into the TCA cycle. HLRCC utilizes glutamine-dependent reductive carboxylation to form citrate. HLRCC, hereditary leiomyomatosis and renal cell carcinoma; FH, fumarate hydratase; AMPK, AMP-activated protein kinase; PHD, prolyl hydroxylase; PDK1, pyruvate dehydrogenase kinase 1.

Figure 2
Figure 2

Schematic representation of the potential association between FH loss and EMT activation in HLRCC. The TET3-mediated demethylation of the miR-200 cluster is blocked as fumarate accumulates as a consequence of FH inactivation, resulting in epigenetic repression of the miR-200ba429 cluster. As a result, Zeb1/2 is triggered, initiating a signaling cascade that contributes to EMT. FH, fumarate hydratase; EMT, Epithelial-mesenchymal transition; HLRCC, hereditary leiomyomatosis and renal cell carcinoma.

Figure 3
Figure 3

FH loss is involved in the DNA damage response in HLRCC. In the nucleus, fumarate accumulation increases the resistance to DNA damage by ionizing radiation (IR) and promotes the non-homologous end-joining upon DNA damage by inhibiting KDM6, a key histone of demethylase involved in the deployment of chromatin for DNA repair. Biallelic inactivation of fumarase in a single tumor cell may prevent the cell from producing fumarate in close proximity to the cellular DNA, lowering genomic stability and leading to the formation of new mutations. The fumarate concentration in a single tumor cell may not be sufficient to stabilize HIF. Furthermore, the proliferation of fumarase deficient cells may shape a tightly packed cell population, allowing fumarate levels to rise to the concentration needed for HIF stabilization. FH, fumarate hydratase; HLRCC, hereditary leiomyomatosis and renal cell carcinoma.

Figure 4
Figure 4

Sustained NRF2 activation in HLRCC. Under normal conditions, NRF2 associates with the Cul3-Rbx1 E3 ubiquitin-ligase substrate KEAP1, which keeps NRF2 primed for ubiquitination and proteasomal degradation. ROS stress induces conformational changes in KEAP1, resulting in NRF2 dissociation. Free NRF2 reaches the nucleus, where it forms dimers with small MAF proteins and binds to AREs regulatory sequences of target genes. NRF2, Nuclear factor erythroid 2-related factor 2; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; AREs, antioxidant responsive elements.

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