UBE2S and UBE2C confer a poor prognosis to breast cancer via downregulation of Numb

Abstract

PurposeUbiquitin-conjugating enzymes E2S (UBE2S) and E2C (UBE2C), which mediate the biological process of ubiquitination, have been widely reported in various cancers. Numb, the cell fate determinant and tumor suppressor, was also involved in ubiquitination and proteasomal degradation. However, the interaction between UBE2S/UBE2C and Numb and their roles in the clinical outcome of breast cancer (BC) are not widely elucidated.MethodsOncomine, Cancer Cell Line Encyclopedia (CCLE), the Human Protein Atlas (HPA) database, qRT-PCR, and Western blot analyses were utilized to analyze UBE2S/UBE2C and Numb expression in various cancer types and their respective normal controls, breast cancer tissues, and breast cancer cell lines. The expression of UBE2S, UBE2C, and Numb in BC patients with different ER, PR, and HER2 status, grades, stages, and survival status was compared. By Kaplan–Meier plotter, we further evaluated the prognostic value of UBE2S, UBE2C, and Numb in BC patients. We also explored the potential regulatory mechanisms underlying UBE2S/UBE2C and Numb through overexpression and knockdown experiments in BC cell lines and performed growth and colony formation assays to assess cell malignancy.ResultsIn this study, we showed that UBE2S and UBE2C were overexpressed while Numb was downregulated in BC, and in BC of higher grade, stage, and poor survival. Compared to hormone receptor negative (HR−) BC cell lines or tissues, HR+ BC demonstrated lower UBE2S/UBE2C and higher Numb, corresponding to better survival. We also showed that increased UBE2S/UBE2C and reduced Numb predicted poor prognosis in BC patients, as well as in ER+ BC patients. In BC cell lines, UBE2S/UBE2C overexpression decreased the level of Numb and enhanced cell malignancy, while knocking down UBE2S/UBE2C demonstrated the opposite effects.ConclusionUBE2S and UBE2C downregulated Numb and enhanced BC malignancy. The combination of UBE2S/UBE2C and Numb could potentially serve as novel biomarkers for BC.

Transcriptomic analysis revealed potential regulatory biomarkers and repurposable drugs for breast cancer treatment

“…Then using these unique common genes, we find 12 hub‐proteins through PPI analysis such as AURKB, TTK, PLK1, NUSAP1, UBE2C, ZWINT, CDCA8, CDC25C, KIF15, CDC45, OIP5 and DEPDC1. Among these, three are most significant such as AURKB, TTK, and PLK1 andseveral researchers identified all of these genes have previously been recognized as oncogenes, possible biomarkers for diagnosing and prognosis of early stage BC such as AURKB, 43 UBE2C, 44 CDCA8, 45 CDC45, 46 KIF15, 47 TTK 48 and PLK1. 49 Besides, the most significant three genes (AURKB, TTK and PLK1) were involved in BC development and served as a potential targets of therapeutic interventions.…”

UBE2C promotes malignancy of cutaneous squamous cell carcinoma

“…21 In breast cancer cells, overexpression of UBE2C has been shown to decrease Numb expression, a tumor suppressor in various cancers, and increase the malignancy of tumor cells. 22 Guo et al 23…”

“…Besides, UBE2C‐mediated ubiquitination and degradation of SIRT1 contribute to the malignant progression of endometrial cancer through epigenetic inhibition of autophagy 21 . In breast cancer cells, overexpression of UBE2C has been shown to decrease Numb expression, a tumor suppressor in various cancers, and increase the malignancy of tumor cells 22 . Guo et al 23 .…”

Role of UBE2C in Brain Cancer Invasion and Dissemination

“…UBE2C overexpression has been shown to have a prognostic value in breast cancer [47,55]. Recently, high levels of this protein have been identified as an independent prognostic marker in breast cancer patients, correlated with poor prognosis, high tumor grade, lymphovascular invasion, lymph node metastases, hormone receptor negativity, HER2 positivity, and stem-like features [56,57,81]. Invasive breast tumors seem to have a higher expression of UBE2C [82].…”