The E3 Ubiquitin Ligase HectD1 Suppresses EMT and Metastasis by Targeting the +TIP ACF7 for Degradation

Duhamel, Stéphanie; Goyette, Marie-Anne; Thibault, Maxime; Filion, Dominic; Gaboury, Louis; Côté, Jean‐François

doi:10.1016/j.celrep.2017.12.096

Cited by 42 publications

(54 citation statements)

References 37 publications

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“…Mice carrying the floxed MACF1 alleles (in B6 background) were acquired through a material transfer agreement between the University of Chicago (USA) and the Northwestern Polytechnical University (China). Construction of the targeting vector was reported previously [5], in which the loxP sites were integrated to excise exons 11,12, and 13 of the Macf1 gene (while in the original literature, the flanked exons were reported as E6 and E7) ( Figure S1A). Mice expressing Cre recombinase under the control of Prx1 (paired related homeobox1) promoter (in B6 background) were acquired from Biocytogen Co., Ltd. (Beijing, China).…”

Section: Generation Of the Macf1 Conditional Knockout (Cko) Mousementioning

confidence: 99%

Mesenchymal MACF1 Facilitates SMAD7 Nuclear Translocation to Drive Bone Formation

Zhao

Qiu

Wang

et al. 2020

Cells

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Microtubule actin crosslinking factor 1 (MACF1) is a large crosslinker that contributes to cell integrity and cell differentiation. Recent studies show that MACF1 is involved in multiple cellular functions such as neuron development and epidermal migration, and is the molecular basis for many degenerative diseases. MACF1 is highly abundant in bones, especially in mesenchymal stem cells; however, its regulatory role is still less understood in bone formation and degenerative bone diseases. In this study, we found MACF1 expression in mesenchymal stem cells (MSCs) of osteoporotic bone specimens was significantly lower. By conditional gene targeting to delete the mesenchymal Macf1 gene in mice, we observed in MSCs decreased osteogenic differentiation capability. During early stage bone development, the MACF1 conditional knockout (cKO) mice exhibit significant ossification retardation in skull and hindlimb, and by adulthood, mesenchymal loss of MACF1 attenuated bone mass, bone microarchitecture, and bone formation capability significantly. Further, we showed that MACF1 interacts directly with SMAD family member 7 (SMAD7) and facilitates SMAD7 nuclear translocation to initiate downstream osteogenic pathways. Hopefully these findings will expand the biological scope of the MACF1 gene, and provide an experimental basis for targeting MACF1 in degenerative bone diseases such as osteoporosis.

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Section: Generation Of the Macf1 Conditional Knockout (Cko) Mousementioning

confidence: 99%

Mesenchymal MACF1 Facilitates SMAD7 Nuclear Translocation to Drive Bone Formation

Zhao

Qiu

Wang

et al. 2020

Cells

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“…Notably, a recent study by Duhamel et al (49) observed that the HECTD1-mediated regulation of ACF7, a +TIPs protein required for cell migration, modulated EMT during metastasis in breast cancer; the decreased expression of HECTD1 promoted ACF7-induced EMT, invasion and metastasis. Thus, the results of the present study, alongside the results from the study by Duhamel et al (49), suggested that HECTD1 may promote EMT through multiple different mechanisms by targeting distinct molecules.…”

Section: Discussionmentioning

confidence: 99%

HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition

et al. 2020

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As a transcription factor, SNAIL plays a crucial role in embryonic development and cancer progression by mediating epithelial-mesenchymal transition (EMT); however, post-translational modifications, such as ubiquitination, which control the degradation of SNAIL have been observed to affect its functional role in EMT. In a previous study by the authors, it was demonstrated that the HECT domain E3 ubiquitin ligase 1 (HECTD1) regulated the dynamic nature of adhesive structures. In the present study, HECTD1 was observed to interact with SNAIL and regulate its stability through ubiquitination, and the knockdown of HECTD1 increased the expression levels of SNAIL. HECTD1 was discovered to contain putative nuclear localization and export signals that facilitated its translocation between the cytoplasm and nucleus, a process regulated by epidermal growth factor (EGF). Treatment with leptomycin B resulted in the nuclear retention of HECTD1, which was associated with the loss of SNAIL expression. The knockdown of HECTD1 in HeLa cells increased cell migration and induced a mesenchymal phenotype, in addition to demonstrating sustained EGF signaling, which was observed through increased phosphorylated ERK expression levels. Under hypoxic conditions, HECTD1 expression levels were decreased by microRNA (miRNA or miR)-210. Upon the observation of genetic abnormalities in the HECTD1 gene in cervical cancer specimens, it was observed that the decreased expression levels of HECTD1 were significantly associated with a poor patient survival. Thus, it was hypothesized that HECTD1 may regulate EMT through the hypoxia/hypoxia inducible factor 1α/miR-210/HECTD1/SNAIL signaling pathway and the EGF/EGF receptor/HECTD1/ERK/SNAIL signaling pathway in cervical cancer. On the whole, the data of the present study indicated that HECTD1 serves as an E3 ubiquitin ligase to mediate the stability of SNAIL proteins.

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“…We identified HECTD1 as LXN associating protein. Because HECTD1 is an E3 ubiquitin ligase, which widely involved in the regulation of cancer invasion 37,38 , this prompted us to hypothesis that HECTD1 may be related to the ubiquitylation of IκBα. Interestingly, HECTD1 may interact with adenomatous polyposis coli (APC), whose dysfunction has been linked to the development of most forms of colorectal cancer 39 .…”

Section: Discussionmentioning

confidence: 99%

Latexin deficiency in mice up-regulates inflammation and aggravates colitis through HECTD1/Rps3/NF-κB pathway

Huang

Yang

et al. 2020

Sci Rep

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The function of Latexin (LXN) in inflammation has attracted attention. However, no data are available regarding its role in colitis. We report that LXN is a suppressor of colitis. LXN deficiency leads to the severity of colitis in DSS-induced mice, and LXN is required for the therapeutic effect of retinoic acid on colitis. Using a proteomics approach, we demonstrate that LXN interacts and forms a functional complex with HECTD1 (an E3 ubiquitin ligase) and ribosomal protein subunit3 (Rps3). IκBα is one of the substrates of HECTD1. Ectopic expression of LXN leads to IκBα accumulation in intestinal epithelial cells, however, LXN knockdown enhances the interaction of HECTD1 and Rps3, contributing to the ubiquitination degradation of IκBα, and subsequently enhances inflammatory response. Thus, our findings provided a novel mechanism underlying LXN modulates colitis via HECTD1/Rps3/NF-κB pathway and significant implications for the development of novel strategies for the treatment of colitis by targeting LXN.

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The E3 Ubiquitin Ligase HectD1 Suppresses EMT and Metastasis by Targeting the +TIP ACF7 for Degradation

Cited by 42 publications

References 37 publications

Mesenchymal MACF1 Facilitates SMAD7 Nuclear Translocation to Drive Bone Formation

Mesenchymal MACF1 Facilitates SMAD7 Nuclear Translocation to Drive Bone Formation

HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition

Latexin deficiency in mice up-regulates inflammation and aggravates colitis through HECTD1/Rps3/NF-κB pathway

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