Regulation of Epithelial-Mesenchymal Transition by E3 Ubiquitin Ligases and Deubiquitinase in Cancer

Inoue, Yasumichi; Itoh, Yoshio; Sato, Koichi; Kawasaki, Fumihiro; Sumita, Chihiro; Tanaka, Takahito; Morishita, Daisuke; Hayashi, Hidetoshi

doi:10.2174/1568009616666151112122126

Cited by 25 publications

(14 citation statements)

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“…USP22 is positively associated with invasion and metastasis of thyroid cancer by altering EMT expression . EMT‐inducing transcriptional factors are extremely labile proteins and tightly regulated by the ubiquitin–proteasome system, which indicates the important role of USPs in controlling EMT . In this study, we showed that USP32 depletion significantly decreased the migration ability of SCLC cells accompanied by increased E‐cadherin and decreased N‐cadherin expression.…”

Section: Discussionmentioning

confidence: 57%

Downregulation of USP32 inhibits cell proliferation, migration and invasion in human small cell lung cancer

Wei²,

et al. 2017

Cell Proliferation

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Section: Discussionmentioning

confidence: 57%

Downregulation of USP32 inhibits cell proliferation, migration and invasion in human small cell lung cancer

Wei²,

et al. 2017

Cell Proliferation

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“…S5). These genes did not emerge as differentially expressed by transcriptome sequencing analysis, but their protein product is known to undergo posttranscriptional regulation (12,13).…”

Section: Molecular Profiling Of Dfsp Evolutionmentioning

confidence: 93%

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Stacchiotti

Astolfi

Gronchi

et al. 2016

Molecular Cancer Research

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Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases.Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target.

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“…It is now generally appreciated that EMT occurs during cancer cell progression and metastasis. 2,3 The EMT is a central process of embryogenesis or normal cell development, in which epithelial (E) cells reach fibroblast-like mesenchymal (M) state. In brief, the fairly round shaped E cells are connected by cell–cell adhesion, facilitating cell layer formation and remain largely static.…”

Section: Resultsmentioning

confidence: 99%

“…1 Recent works have shown that cancers can evolve non-genetically and are able to make the epithelial-mesenchymal transition (EMT), providing with high motility to form metastasis of surrounding and other far-from-connected tissues. 2,3 It is, therefore, conceivable why most, if not all, invasive and non-invasive treatment strategies, based on the predominant “average cell” (all cells being equal) approach, to tackle and control the complexity of cancer succumb to cell proliferations. To understand the complexities of dynamic cancer response, and to regulate them successfully, experimental approaches alone are insufficient.…”

Section: Introductionmentioning

confidence: 99%

Defining rules for cancer cell proliferation in TRAIL stimulation

2019

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Owing to their self-organizing evolutionary plasticity, cancers remain evasive to modern treatment strategies. Previously, for sensitizing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant human fibrosarcoma (HT1080), we developed and validated a dynamic computational model that showed the inhibition of protein kinase (PK)C, using bisindolylmaleimide (BIS) I, enhances apoptosis with 95% cell death. Although promising, the long-term effect of remaining ~ 5% cells is a mystery. Will they remain unchanged or are they able to proliferate? To address this question, here we adopted a discrete spatiotemporal cellular automata model utilizing simple rules modified from the famous “Conway’s game of life”. Based on three experimental initializations: cell numbers obtained from untreated (high), treatment with TRAIL only (moderate), and treatment with TRAIL and BIS I (low), the simulations show cell proliferation in time and space. Notably, when all cells are fixed in their initial space, the proliferation is rapid for high and moderate cell numbers, however, slow and steady for low number of cells. However, when mesenchymal-like random movement was introduced, the proliferation becomes significant even for low cell numbers. Experimental verification showed high proportion of mesenchymal cells in TRAIL and BIS I treatment compared with untreated or TRAIL only treatment. In agreement with the model with cell movement, we observed rapid proliferation of the remnant cells in TRAIL and BIS I treatment over time. Hence, our work highlights the importance of mesenchymal-like cellular movement for cancer proliferation. Nevertheless, re-treatment of TRAIL and BIS I on proliferating cancers is still largely effective.

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Regulation of Epithelial-Mesenchymal Transition by E3 Ubiquitin Ligases and Deubiquitinase in Cancer

Cited by 25 publications

References 0 publications

Downregulation of USP32 inhibits cell proliferation, migration and invasion in human small cell lung cancer

Downregulation of USP32 inhibits cell proliferation, migration and invasion in human small cell lung cancer

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Defining rules for cancer cell proliferation in TRAIL stimulation

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