Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues

Moschos, Stergios J.; Jukic, D.M.; Athanassiou, Charalambos; Bhargava, Rohit; Đačić, Sanja; Wang, Xiaolei; Kuan, Shih Fan; Fayewicz, Shelley L.; Galambos, Csaba; Acquafondata, Marie; Dhir, Rajiv; Becker, Dorothea

doi:10.1016/j.humpath.2010.02.007

Cited by 82 publications

(75 citation statements)

References 31 publications

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“…Our results show enhanced expression of Ubc9 in ovarian tumors compared to matched normal tissues (Figure 3 B). This agrees with our results obtained using breast tumor tissue samples [34] and previous studies that documented higher levels of Ubc9 expression in several cancers compared with their normal tissue counterparts [35][36][37][38].…”

Section: Ubc9 Is Expressed At Elevated Levels In Brca1 Mutant Hgsoc supporting

confidence: 93%

“…Ubc9 has been shown to be upregulated in multiple cancers and to promote invasion and metastasis in estrogen receptor positive breast cancer cells [35][36][37][38][39]. As mentioned earlier, we observed overexpression of Ubc9 in BRCA1 mutant TNBC cells and HGSOC cells.…”

Section: Knockdown Of Ubc9 Inhibits Proliferation and Migration Of Hgsupporting

confidence: 83%

“…Recently, there are several reports connecting protein SUMOylation and cancer. Elevated levels of Ubc9 have been found in several cancers and are associated with poor clinical outcome [45][46][47][48][49]. Our group has previously reported that Wild type BRCA1a/1b proteins unlike the pathogenic mutants to bind Ubc9, a sole SUMO conjugase and perform its function as a tumor suppressor in TNBC and ovarian cancer cells [34,41].…”

Section: Discussionmentioning

confidence: 99%

“…Our group has previously reported that Wild type BRCA1a/1b proteins unlike the pathogenic mutants to bind Ubc9, a sole SUMO conjugase and perform its function as a tumor suppressor in TNBC and ovarian cancer cells [34,41]. Although Ubc9 is ubiquitously expressed in normal cells, it was shown to be over-expressed in ovarian, lung, head and neck, melanoma and breast cancers [35][36][37][38]44]. In fact, Ubc9 expression was found to correlate with poor clinical outcome in Nigerian women with breast cancer [50].…”

Section: Discussionmentioning

confidence: 99%

“…Both BRCA1/BRCA1a K109R and disease associated C61G mutants, which are localized mainly in the cytoplasm, fail to suppress the growth of TNBC and ovarian cancer cells [34]. Ubc9 has been shown to play an important role in both tumor progression and resistance to chemotherapy [35][36][37][38]. In fact, Ubc9 was found to act as both a positive and negative regulator of proliferation and transformation of HMGA1 proteins [39].…”

Section: Introductionmentioning

confidence: 99%

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BRCA1 Mutation Leads to Deregulated Ubc9 Levels which Triggers Proliferation and Migration of Patient-Derived High Grade Serous Ovarian Cancer and Triple Negative Breast Cancer Cells

Footman

Qin

et al. 2016

IJCDT

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Women who carry a germline mutation in BRCA1 gene typically develop triple negative breast cancers (TNBC) and high grade serous ovarian cancers (HGSOC). Previously, we reported that wild type BRCA1 proteins, unlike the disease-associated mutant BRCA1 proteins to bind the sole sumo E2-conjugating enzyme Ubc9. In this study, we have used clinically relevant cell lines with known BRCA1 mutations and report the in-vivo association of BRCA1 and Ubc9 in normal mammary epithelial cells but not in BRCA1 mutant HGSOC and TNBC cells by immunofluorescence analysis. BRCA1-mutant HGSOC/TNBC cells and ovarian tumor tissues showed increased expression of Ubc9 compared to BRCA1 reconstituted HGSOC, normal mammary epithelial cells and matched normal ovarian tissues. Knockdown of Ubc9 expression resulted in decreased proliferation and migration of BRCA1 mutant TNBC and HGSOC cells. This is the first study demonstrating the functional link between BRCA1 mutation, high Ubc9 expression and increased migration of HGSOC and TNBC cells. High Ubc9 expression due to BRCA1 mutation may trigger an early growth and transformation advantage to normal breast and ovarian epithelial cells resulting in aggressive cancers. Future work will focus on studying whether Ubc9 expression could show a positive correlation with BRCA1 linked HGSOC and basal like TNBC phenotype.This is an open

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Section: Ubc9 Is Expressed At Elevated Levels In Brca1 Mutant Hgsoc supporting

confidence: 93%

Section: Knockdown Of Ubc9 Inhibits Proliferation and Migration Of Hgsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

BRCA1 Mutation Leads to Deregulated Ubc9 Levels which Triggers Proliferation and Migration of Patient-Derived High Grade Serous Ovarian Cancer and Triple Negative Breast Cancer Cells

Footman

Qin

et al. 2016

IJCDT

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Spatiotemporal distribution of SUMOylation components during mouse brain development

Hasegawa

Yoshida

Nakamura

et al. 2014

J of Comparative Neurology

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Posttranslational modification of proteins might play an important role in brain cellular dynamics via the rapid turnover or functional change of critical proteins controlling neuronal differentiation or synaptic transmission. Small ubiquitin-like modifier protein (SUMO) is a family of ubiquitin-like small proteins that are covalently attached to target proteins to modify their function posttranslationally. Many cellular processes, such as transcription and protein trafficking, are regulated by SUMOylation, but its functional significance in the brain remains unclear. Although developmental regulation of SUMOylation levels in rat brain was recently demonstrated, no comparative immunohistochemical analysis of the cellular distribution profiles of SUMOylation components, including SUMO1, SUMO2/3, and Ubc9, has been undertaken so far. The present study used immunohistochemical and immunoblot analysis with the different developmental stages of mice and demonstrated the developmentally regulated distribution of SUMO1, SUMO2/3, and Ubc9 in the brain. During embryonic development, SUMOylation by SUMO1 and SUMO2/3 occurred in the nucleoplasm of nestin-positive neural stem cells. Although the total amount of SUMO-modified proteins decreased during postnatal brain development, intense and persistent accumulation of SUMO2/3 was detected throughout life in neural progenitor populations in neurogenic regions, including the subventricular zone and the hippocampal subgranular zone. In contrast, many neurons in the adult brain accumulated SUMO1 rather than SUMO2/3. Heavy immunoreactivity of SUMO1 was found in large projection neurons in the brainstem, whereas SUMO2/3 was almost absent from these areas. This heterogeneous distribution implies that both proteins play a specific and unique role in the brain.

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S-adenosyl methionine regulates ubiquitin-conjugating enzyme 9 protein expression and sumoylation in murine liver and human cancers

Tomasi

Ramani

et al. 2012

Hepatology

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Background and rationale Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and overexpressed in several malignancies but its expression in hepatocellular carcinoma (HCC) is unknown. Hepatic S-adenosylmethionine (SAMe) level falls in methionine adenosyltransferase 1A (Mat1a) knockout (KO) mice, which develop HCC, and in ethanol fed mice. Here we examined regulation of Ubc9 by SAMe in murine liver and human HCC, breast and colon carcinoma cell lines and specimens. Methods Real-time PCR and Western blotting measured gene and protein expression, respectively. Immunoprecipitation followed by Western blotting examined protein-protein interactions. Results Ubc9 expression is increased in HCC and when hepatic SAMe level falls. SAMe treatment in Mat1a KO mice reduced Ubc9 protein but not mRNA level and lowered sumoylation. Similarly, treatment of liver cancer cell lines HepG2 and Huh-7, colon cancer cell line RKO and breast cancer cell line MCF-7 with SAMe or its metabolite methylthioadenosine (MTA) reduced only Ubc9 protein level. Ubc9 post-translational regulation is unknown. Ubc9 sequence predicts a possible phosphorylation site by cell division cycle 2 (Cdc2), which directly phosphorylated recombinant Ubc9. Mat1a KO mice have higher phospho-Ubc9 level, which normalized after SAMe treatment. SAMe and MTA treatment lowered Cdc2 mRNA and protein levels, phospho-Ubc9 and protein sumoylation in liver, colon and breast cancer cells. Serine 71 of Ubc9 is required for phosphorylation, interaction with Cdc2 and protein stability. Cdc2, Ubc9 and phospho-Ubc9 levels are increased in human liver, breast and colon cancers. Conclusions Cdc2 expression is increased and Ubc9 is hyperphosphorylated in several cancers and this represents a novel mechanism to maintain high Ubc9 protein expression that can be inhibited by SAMe and MTA.

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Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues

Cited by 82 publications

References 31 publications

BRCA1 Mutation Leads to Deregulated Ubc9 Levels which Triggers Proliferation and Migration of Patient-Derived High Grade Serous Ovarian Cancer and Triple Negative Breast Cancer Cells

BRCA1 Mutation Leads to Deregulated Ubc9 Levels which Triggers Proliferation and Migration of Patient-Derived High Grade Serous Ovarian Cancer and Triple Negative Breast Cancer Cells

Spatiotemporal distribution of SUMOylation components during mouse brain development

S-adenosyl methionine regulates ubiquitin-conjugating enzyme 9 protein expression and sumoylation in murine liver and human cancers

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