Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers

Xie, Shangdan; Xia, Lu; Song, Yizuo; Liu, Hejing; Wang, Zhiwei; Zhu, Xueqiong

doi:10.3389/fonc.2021.774648

Cited by 27 publications

(29 citation statements)

References 95 publications

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“…In addition to CDKN1A , HEB and E2A co-occupy three TSG loci, APC , a haplo-insufficient tumor suppressor, ZMYND11 a chromatin reader and tumor suppressor in breast cancer ( 115 ) and CUX1 , a homeodomain transcription regulator and haploinsufficient tumor suppressor ( 116 ). HEB is also found to occupy three other TSGenes, MYBPP1A , potentially involved in nucleolar stress, NEDD4L , an E3 ligase with tumor suppressor function ( 117 ) and PLCB3 , encoding phospholipase C beta 3 (phosphatidylinositol-specific), involved in G-protein-linked receptor-mediated signal transduction ( Figure 6H ). These additional targets may account for the more prominent role of HEB as a tumor suppressor in response to the oncogenic stress induced by SCL and LMO1, exactly at the β-selection checkpoint controlled by HEB.…”

Section: Discussionmentioning

confidence: 99%

Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

et al. 2022

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Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.

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Section: Discussionmentioning

confidence: 99%

Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

et al. 2022

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“…Moreover, NEDD4L has been shown to be involved in both oncogenesis and tumor suppression (X. Y. Guo et al, 2022; Xie et al, 2021). However, it is unclear if a specific AS isoform of NEDD4L is responsible for regulating TGFβ signaling in TNBC tumors, where it has the potential to drive multiple aspects of tumor progression.…”

Section: Resultsmentioning

confidence: 99%

Development and validation of an AI/ML platform for the discovery of splice-switching oligonucleotide targets

Fronk

Manzanares

Zheng

et al. 2022

Preprint

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This study demonstrates the value that artificial intelligence/machine learning (AI/ML) provides for the identification of novel and verifiable splice-switching oligonucleotide (SSO) targets in-silico. SSOs are antisense compounds that act directly on pre-mRNA to modulate alternative splicing (AS). To leverage the potential of AS research for therapeutic development, we created SpliceLearnTM, an AI/ML algorithm for the identification of modulatory SSO binding sites on pre-mRNA. SpliceLearn also predicts the identity of specific splicing factors whose binding to pre-mRNA is blocked by SSOs, adding considerable transparency to AI/ML-driven drug discovery and informing biological insights useful in further validation steps. Here we predicted NEDD4L exon 13 (NEDD4Le13) as a novel target in triple negative breast cancer (TNBC) and computationally designed an SSO to modulate NEDD4Le13. Targeting NEDD4Le13 with this SSO decreased the proliferative and migratory behavior of TNBC cells via downregulation of the TGFβ pathway. Overall, this study illustrates the ability of AI/ML to extract actionable insights from RNA-seq data. SpliceLearn is part of the SpliceCore® platform, an AI/ML predictive ensemble for AS-based drug target discovery.

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“…The ubiquitin-proteasome system is composed of ubiquitin activating enzyme (E1), ubiquitin conjugation enzyme (E2) and ubiquitin ligase (E3). Ubiquitin is activated by E1 and transferred from E2 to substrate mediated by E3 (Xie et al, 2021). E3 ligases can be divided into three classes according to its structure and ubiquitin transfer mechanism: Really interesting new gene (RING)-type E3 ligases, Homologous to E6-AP COOH terminus (HECT)-type E3 ligases and Ring between Ring (RBR)-type E3 ligases (Qie, 2022).…”

Section: Introductionmentioning

confidence: 99%

The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response

et al. 2022

Front. Physiol.

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E3 ubiquitin ligases, an important part of ubiquitin proteasome system, catalyze the covalent binding of ubiquitin to target substrates, which plays a role in protein ubiquitination and regulates different biological process. DNA damage response (DDR) is induced in response to DNA damage to maintain genome integrity and stability, and this process has crucial significance to a series of cell activities such as differentiation, apoptosis, cell cycle. The NEDD4 family, belonging to HECT E3 ubiquitin ligases, is reported as regulators that participate in the DDR process by recognizing different substrates. In this review, we summarize recent researches on NEDD4 family members in the DDR and discuss the roles of NEDD4 family members in the cascade reactions induced by DNA damage. This review may contribute to the further study of pathophysiology for certain diseases and pharmacology for targeted drugs.

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Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers

Cited by 27 publications

References 95 publications

Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

Development and validation of an AI/ML platform for the discovery of splice-switching oligonucleotide targets

The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response

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