Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates
            <i>MYCN</i>
            -amplified neuroblastoma growth

Guo, Yufeng; Duan, Jiang‐Jie; Wang, Jun; Lin, Li; Wang, Di; Liu, Xun-Zhou; Yang, Jing; Zhang, Huarong; Lv, Jing; Yang, Yongjun; Yang, Zeyu; Cai, Jingyi; Liao, Xuemei; Tang, Tao; Huang, Tingting; Wu, Feng; Yang, Xianyan; Wen, Qian; Bian, Xiu‐Wu; Yu, Shanshan

doi:10.1126/scitranslmed.aax8694

Cited by 29 publications

(38 citation statements)

References 81 publications

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“…These findings demonstrated that the overexpression of ALDH18A1 decreased the rate of ACD and induced SCD, whereas the knockdown of ALDH18A1 increased the rate of ACD (34). Furthermore, molecular docking was applied to screen ALDH18A1 inhibitors, and the findings obtained showed that one compound, termed YG1702, from the approximately >200,000 compounds tested specifically inhibited the function of ALDH18A1 (34). Therefore, YG1702 has potential as a therapeutic drug that induces ACD and reduces the malignant transformation of MYCN-amplified neuroblastoma cells.…”

Section: Aldh18a1mentioning

confidence: 84%

“…Aldehyde dehydrogenase family 18 member A1 (ALDH18A1) was originally identified as the key enzyme for the synthesis of proline from glutamate, which catalyzes the coupled phosphorylation and reduction conversion of glutamate to β-pyrroline-5-carboxylate (P5C) and plays a critical role in regulating glutamine metabolism (33). A recent study revealed that ALDH18A1 formed a positive feedback loop with MYCN and was involved in the malignant transformation of neuroblastoma cells (Figure 1) (34). These findings demonstrated that the overexpression of ALDH18A1 decreased the rate of ACD and induced SCD, whereas the knockdown of ALDH18A1 increased the rate of ACD (34).…”

Section: Aldh18a1mentioning

confidence: 99%

“…A recent study revealed that ALDH18A1 formed a positive feedback loop with MYCN and was involved in the malignant transformation of neuroblastoma cells (Figure 1) (34). These findings demonstrated that the overexpression of ALDH18A1 decreased the rate of ACD and induced SCD, whereas the knockdown of ALDH18A1 increased the rate of ACD (34). Furthermore, molecular docking was applied to screen ALDH18A1 inhibitors, and the findings obtained showed that one compound, termed YG1702, from the approximately >200,000 compounds tested specifically inhibited the function of ALDH18A1 (34).…”

Section: Aldh18a1mentioning

confidence: 99%

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The Role of MYCN in Symmetric vs. Asymmetric Cell Division of Human Neuroblastoma Cells

2020

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Asymmetric cell division (ACD) is an important physiological event in the development of various organisms and maintenance of tissue homeostasis. ACD produces two different cells in a single cell division: a stem/progenitor cell and differentiated cell. Although the balance between self-renewal and differentiation is precisely controlled, disruptions to ACD and/or enhancements in the self-renewal division (symmetric cell division: SCD) of stem cells resulted in the formation of tumors in Drosophila neuroblasts. ACD is now regarded as one of the characteristics of human cancer stem cells, and is a driving force for cancer cell heterogeneity. We recently reported that MYCN controls the balance between SCD and ACD in human neuroblastoma cells. In this mini-review, we discuss the mechanisms underlying MYCN-mediated cell division fate.

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Section: Aldh18a1mentioning

confidence: 84%

Section: Aldh18a1mentioning

confidence: 99%

Section: Aldh18a1mentioning

confidence: 99%

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The Role of MYCN in Symmetric vs. Asymmetric Cell Division of Human Neuroblastoma Cells

2020

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“…Although the specific transcriptional tar-get(s) of MYCN currently remain unclear except for the high mobility group A1 (HMGA1) oncogene [32], several molecular pathways have been identified in MYCN-mediated cell division fate (Figure 2) [17]. MYCN and ALDH18A1 form a positive feedback loop for their transcriptional expression [33]. This positive feedback loop effectively induces symmetric cell division (SCD).…”

Section: Mycn Regulates Cell Division Fatementioning

confidence: 99%

Analysis of Asymmetric Cell Division Using Human Neuroblastoma Cell Lines as a Model System

Izumi¹,

Kaneko

Nakagawara

2021

Symmetry

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Neuroblastoma is one of the most common childhood solid tumors and develops from neural stem cells that normally comprise the embryonic structure termed the neural crest. Human neuroblastoma cell lines have special properties as they exhibit cell growth and are induced to become mature neurons by drugs such as retinoid. Therefore, we examined asymmetric cell division (ACD) using human neuroblastoma cells as an ACD model, and confirmed that ACD in human cancer cells is evolutionally conserved. Furthermore, we demonstrated that MYCN is involved in cell division fate. We introduce the brief history of ACD study using neuroblastoma cell lines and discuss why human neuroblastoma cells are an ideal model system for clarifying the mechanism of ACD.

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“…MYCN is amplified or overexpressed in one third of children with neuroblastoma, and, is a driver in several other human cancer types [ 1 , 5 , 6 ]. We and others have shown that increased MYCN protein stability is acquired by neuroblastoma cells, even in the presence of MYCN amplification, by multiple feed-forward expression loops involving MYCN trans-activation and -repression target genes [ 6 – 8 ]. MYCN protein stability is tightly regulated in normal cells through several post-translational modifications, MYCN binding proteins, and the ubiquitin ligase SCF-FBXW7 [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma

et al. 2021

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Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.

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Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN -amplified neuroblastoma growth

Cited by 29 publications

References 81 publications

The Role of MYCN in Symmetric vs. Asymmetric Cell Division of Human Neuroblastoma Cells

The Role of MYCN in Symmetric vs. Asymmetric Cell Division of Human Neuroblastoma Cells

Analysis of Asymmetric Cell Division Using Human Neuroblastoma Cell Lines as a Model System

A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma

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