Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models

Olaizola, Paula; Lee, Pui Yuen; Fernández‐Barrena, Maite G.; Álvarez, Laura; Cadamuro, Massimiliano; Azkargorta, Mikel; O’Rourke, Colm J.; Caballero-Camino, Francisco J.; Olaizola, Irene; Macı́as, Rocı́o I.R.; Marin, José J.G.; Serrano‐Maciá, Marina; Martínez‐Chantar, María Luz; Avila, Matı́as A.; Aspichueta, Patricia; Calvisi, Diego F.; Evert, Matthias; Fabris, Luca; Castro, Rui E.; Elortza, Félix; Andersen, Jesper B.; Bujanda, Luís; Rodrigues, Pedro M.

doi:10.1016/j.jhep.2022.02.007

Cited by 16 publications

(33 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the role of post-translational modification of proteins during tumorigenesis in CCA has been recently described, focusing on NEDDylation. [136] Protein NEDDylation refers to the covalent and reversible attachment of the neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8), to a lysine residue in the substrate protein. [137] This process is catalyzed by a 3-step enzymatic cascade that involves the NEDD8-activating enzyme E1 (NAE1) and leads to the inability of target proteins to form multi-protein complexes and therefore compromises their functionality.…”

Section: Cafs and Neddylationmentioning

confidence: 99%

See 1 more Smart Citation

Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma

et al. 2023

Self Cite

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance.CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumorpromoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumorrestricting properties. To elucidate the complexity and potentials of cancerassociated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.

show abstract

Section: Cafs and Neddylationmentioning

confidence: 99%

“…[136] Of note, the pharmacological inhibition of NEDDylation in CAFs reduces their viability, demonstrating the importance of this pathway in the TME of CCA. [136] These recent findings highlight the putative role of NEDDylation in the regulation of the TME and opens to new possibilities for therapy.…”

Section: Cafs and Neddylationmentioning

confidence: 99%

Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…MLN4924 has shown anticancer effects in preclinical adult and pediatric tumor models 17,[51][52][53][54] and good tolerability in Phase I clinical trials as monotherapy and in combination studies in adult cancer patients 40,[55][56][57][58]. Two Phase I studies are ongoing using this agent in combinatorial approaches also in the pediatric cancer setting involving patients with leukemia/lymphoma (NCT03349281, NCT03813147).…”

Section: Discussionmentioning

confidence: 99%

A MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting

Pomella

Cassandri

Cossetti³

et al. 2022

Preprint

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS) is a pediatric mesenchymal-derived malignancy encompassing Fusion Positive (FP)-RMS expressing PAX3/7-FOXO1 and Fusion Negative (FN)-RMS often mutated in the RAS pathway. RMS expresses the master myogenic transcription factor MYOD that, paradoxically, in the tumor context is essential for tumor cell growth and survival. We identify here SKP2, an oncogenic E3-ubiquitin ligase of the SCF/CRL1 complex, as a critical driver of tumorigenesis downstream of MYOD in FN-RMS. SKP2 is overexpressed in RMS at the highest levels among several adult and pediatric cancers and its expression is maintained by MYOD through an intronic enhancer within the gene, in loop with its promoter. Mechanistically, in FN-RMS cells SKP2 functions by directly targeting p27Kip1 and p57Kip2 promoting their degradation. SKP2 knockdown causes cell cycle arrest by enhancing p27Kip1 and promotes differentiation by increasing p57Kip2, which in turn stabilizes MYOD. This leads to MYOD and MYOG increase and unlocks a myogenic program resulting in de novo expression of terminal muscle differentiation markers and cell fusion. SKP2 depletion strongly affects stemness and anchorage-independence features and prevents tumor growth. The investigational NEDDylation inhibitor MLN4924 (Pevonedistat) hampers SKP2 functions restraining FN-RMS cell survival and tumor growth. Our results uncover a MYOD-SKP2 axis crucial for the crosstalk between transcriptional and post-translational mechanisms that contribute to FN-RMS tumorigenesis and broaden the understanding of MYOD function. Furthermore, they suggest inhibition of NEDDylation as a potential therapeutic approach in this tumor.

show abstract

“…In multiple cancers, overactivation of the neddylation pathway leads to elevated global neddylation of substrates, such as cullins, and consequent accumulation of tumor suppressors, thereby promoting tumorigenesis and development [25][26][27][28]. Targeting the overactivated protein neddylation pathway has been proven to be an effective anti-tumor strategy.…”

Section: Introductionmentioning

confidence: 99%

“…When bound to the active site of UBA3, MLN4924 forms a stable covalent adduct with NEDD8 to block further enzymatic processes [30]. It achieves potent anti-tumor effects by inducing cell cycle arrest, apoptosis, or senescence of tumor cells, or affecting the functions of multiple components of the tumor microenvironment [28,29,[31][32][33][34][35][36][37]. MLN4924 has been evaluated in Phase I/II clinical trials for treating various solid tumors and hematologic cancers [38][39][40][41][42][43][44].…”

Section: Introductionmentioning

confidence: 99%

NEDD8-conjugating enzyme E2s: critical targets for cancer therapy

et al. 2023

View full text Add to dashboard Cite

NEDD8-conjugating enzymes, E2s, include the well-studied ubiquitin-conjugating enzyme E2 M (UBE2M) and the poorly characterized ubiquitin-conjugating enzyme E2 F (UBE2F). UBE2M and UBE2F have distinct and prominent roles in catalyzing the neddylation of Cullin or non-Cullin substrates. These enzymes are overexpressed in various malignancies, conferring a worse overall survival. Targeting UBE2M to influence tumor growth by either modulating several biological responses of tumor cells (such as DNA-damage response, apoptosis, or senescence) or regulating the anti-tumor immunity holds strong therapeutic potential. Multiple inhibitors that target the interaction between UBE2M and defective cullin neddylation protein 1 (DCN1), a co-E3 for neddylation, exhibit promising anti-tumor effects. By contrast, the potential benefits of targeting UBE2F are still to be explored. It is currently reported to inhibit apoptosis and then induce cell growth; hence, targeting UBE2F serves as an effective chemo-/radiosensitizing strategy by triggering apoptosis. This review highlights the most recent advances in the roles of UBE2M and UBE2F in tumor progression, indicating these E2s as two promising anti-tumor targets.

show abstract

Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models

Cited by 16 publications

References 19 publications

Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma

Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma

A MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting

NEDD8-conjugating enzyme E2s: critical targets for cancer therapy

Contact Info

Product

Resources

About