TIF1γ Protein Regulates Epithelial-Mesenchymal Transition by Operating as a Small Ubiquitin-like Modifier (SUMO) E3 Ligase for the Transcriptional Regulator SnoN1

ABSTRACTThyroid hormone receptor interactor 12 (TRIP12) is an E3 ligase most notably involved in the proteolytic degradation of the tumor suppressor p14ARF. Through this process, it is proposed that TRIP12 plays an oncogenic role in tumor initiation and growth. However, its role in other cancer processes such as metastasis is unknown. In this study, using publicly available cancer patient datasets, we found TRIP12 to be associated with distant metastasis-free survival in breast cancer, suggesting a contrary cancer process inhibitory role in metastasis. Following TRIP12 depletion in the MCF10A breast epithelial cell model, an epithelial-mesenchymal transition (EMT) shift occurred with concomitant changes in EMT cell adhesion markers identified through RNA-seq. In line with EMT changes, TRIP12-depleted cells lose polarity and dislodge from bulk cells at a higher frequency. Furthermore, ectopic TRIP12 expression sensitized cells to anoikis, a major barrier against metastasis. Mechanistically, TRIP12 suppresses EMT through inhibiting ZEB1/2 gene expression and ZEB1/2 depletion rescues EMT markers and cellular behavior. Overall, our study delineates TRIP12’s role in inhibition of EMT and metastasis-related processes, and implies a suppression role in breast cancer metastasis.

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SUMO E3 ligase CBX4 regulates hTERT-mediated transcription of CDH1 and promotes breast cancer cell migration and invasion

Biochemical Journal ◽

10.1042/bcj20200359 ◽

2020 ◽

Vol 477 (19) ◽

pp. 3803-3818 ◽

Cited By ~ 1

Author(s):

Sulagna Sanyal ◽

Payel Mondal ◽

Sabyasachi Sen ◽

Sumita Sengupta (Bandyopadhyay) ◽

Chandrima Das

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

E3 Ligase ◽

Telomerase Activity ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Sumo E3 Ligase ◽

E Cadherin

hTERT, the catalytic component of the human telomerase enzyme, is regulated by post-translational modifications, like phosphorylation and ubiquitination by multiple proteins which remarkably affects the overall activity of the enzyme. Here we report that hTERT gets SUMOylated by SUMO1 and polycomb protein CBX4 acts as the SUMO E3 ligase of hTERT. hTERT SUMOylation positively regulates its telomerase activity which can be inhibited by SENP3-mediated deSUMOylation. Interestingly, we have established a new role of hTERT SUMOylation in the repression of E-cadherin gene expression and consequent triggering on the epithelial-mesenchymal-transition (EMT) program in breast cancer cells. We also observed that catalytically active CBX4, leads to retention of hTERT/ZEB1 complex onto E-cadherin promoter leading to its repression through hTERT-SUMOylation. Further through wound healing and invasion assays in breast cancer cells, we showed the tumor promoting ability of hTERT was significantly compromised upon overexpression of SUMO-defective mutant of hTERT. Thus our findings establish a new post-translational modification of hTERT which on one hand is involved in telomerase activity maintenance and on the other hand plays a crucial role in the regulation of gene expression thereby promoting migration and invasion of breast cancer cells.

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Cbx4: A new guardian of p63’s domain of epidermal control

The Journal of Cell Biology ◽

10.1083/jcb.201512032 ◽

2015 ◽

Vol 212 (1) ◽

pp. 9-11 ◽

Cited By ~ 4

Author(s):

Idan Cohen ◽

Elena Ezhkova

Keyword(s):

Cell Lineage ◽

E3 Ligase ◽

Transcriptional Regulator ◽

Cell Biol ◽

Epigenetic Regulators ◽

Sumo E3 Ligase

Epigenetic regulators are essential for cell lineage choices during development. In this issue, Mardaryev et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201506065) show that Polycomb subunit Cbx4 acts downstream of transcriptional regulator p63 to maintain epidermal progenitor identity and proliferation in the developing epidermis via Polycomb-dependent and -independent SUMO E3 ligase activities.

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The oncogenic E3 ligase TRIP12 suppresses epithelial–mesenchymal transition (EMT) and mesenchymal traits through ZEB1/2

Cell Death Discovery ◽

10.1038/s41420-021-00479-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Kwok Kin Lee ◽

Deepa Rajagopalan ◽

Shreshtha Sailesh Bhatia ◽

Roberto Tirado-Magallanes ◽

Wee Joo Chng ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Thyroid Hormone Receptor ◽

Epithelial Mesenchymal Transition ◽

E3 Ligase ◽

Breast Cancer Metastasis ◽

Cellular Motility ◽

Rna Seq ◽

Free Survival ◽

Mesenchymal Transition

AbstractThyroid hormone receptor interactor 12 (TRIP12) is an E3 ligase most notably involved in the proteolytic degradation of the tumor suppressor p14ARF. Through this process, it is proposed that TRIP12 plays an oncogenic role in tumor initiation and growth. However, its role in other cancer processes is unknown. In this study, using publicly available cancer patient datasets, we found TRIP12 to be associated with distant metastasis-free survival in breast cancer, suggesting an inhibitory role in metastasis. Following TRIP12 depletion, an epithelial-mesenchymal transition (EMT) shift occurred with concomitant changes in EMT cell adhesion markers identified through RNA-seq. In line with EMT changes, TRIP12-depleted cells gained mesenchymal traits such as loss of cell polarity, dislodgement from bulk cells at a higher frequency, and increased cellular motility. Furthermore, ectopic TRIP12 expression sensitized cells to anoikis. Mechanistically, TRIP12 suppresses EMT through inhibiting ZEB1/2 gene expression, and ZEB1/2 depletion rescues EMT markers and mesenchymal behavior. Overall, our study delineates TRIP12’s role in inhibition of EMT and implies a potential suppressive role in breast cancer metastasis.

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ELK1 Promotes Epithelial-Mesenchymal Transition and the Progression of Lung Adenocarcinoma by Upregulating B7-H3

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/2805576 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Ting-ting Yu ◽

Tao Zhang ◽

Fei Su ◽

Ying-long Li ◽

Li Shan ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Transcriptional Regulator ◽

Mesenchymal Transition ◽

Poor Patient ◽

Patient Prognosis

In previous studies, we found that B7 homolog 3 (B7-H3) was highly expressed in lung adenocarcinoma (LUAD) and promoted epithelial-to-mesenchymal transition (EMT) of LUAD cells. However, the underlying molecular mechanism is unclear. This study is aimed at evaluating the role of Ets-like protein 1 (ELK1) as a transcriptional regulator of B7-H3 for mediating the development and progression of LUAD in vitro and in vivo. We confirmed that ELK1 is highly expressed in LUAD and is associated with poor patient prognosis. ELK1 was found to promote proliferation, invasion, migration, and EMT of LUAD cells through in vivo and in vitro experiments. In terms of mechanism, ELK1 binds to the B7-H3 promoter region and induces the upregulation of B7-H3 in LUAD. Our data suggest that ELK1 plays an important role in the development of LUAD and could be used as a prognostic marker and therapeutic target for LUAD.

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The NFκB subunit RELA is a master transcriptional regulator of the committed epithelial-mesenchymal transition in airway epithelial cells

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.003662 ◽

2018 ◽

Vol 293 (42) ◽

pp. 16528-16545 ◽

Cited By ~ 15

Author(s):

Bing Tian ◽

Steven G. Widen ◽

Jun Yang ◽

Thomas G. Wood ◽

Andrzej Kudlicki ◽

...

Keyword(s):

Epithelial Cells ◽

Epithelial Mesenchymal Transition ◽

Transcriptional Regulator ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Mesenchymal Transition

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Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Molecular Biology of the Cell ◽

10.1091/mbc.e07-03-0249 ◽

2007 ◽

Vol 18 (9) ◽

pp. 3533-3544 ◽

Cited By ~ 198

Author(s):

Takuya Shirakihara ◽

Masao Saitoh ◽

Kohei Miyazono

Keyword(s):

Cancer Progression ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Transcriptional Regulator ◽

Differential Regulation ◽

Mesenchymal Transition ◽

Id Proteins ◽

Direct Binding ◽

E Cadherin

Epithelial–mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-β in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-β–induced EMT. In this study, we show that expression of the δEF1 family proteins, δEF1 (ZEB1) and SIP1, is gradually increased by TGF-β with expression profiles reciprocal to that of E-cadherin. SIP1 and δEF1 each dramatically down-regulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing of the expression of both SIP1 and δEF1, but not either alone, completely abolished TGF-β–induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and δEF1. TGF-β–induced the expression of Ets1, which in turn activated δEF1 promoter activity. Moreover, up-regulation of SIP1 and δEF1 expression by TGF-β was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-β– and Ets1-induced up-regulation of δEF1. Taken together, these findings suggest that the δEF1 family proteins, SIP1 and δEF1, are necessary, but not sufficient, for TGF-β–induced EMT and that Ets1 induced by TGF-β may function as an upstream transcriptional regulator of SIP1 and δEF1.

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