Ubc9 promotes breast cell invasion and metastasis in a sumoylation-independent manner

Abstract

Ubc9 is an E2 conjugating enzyme that transfers the activated SUMO (small ubiquitin-related modifier) to protein substrates, and thus it plays a critical role in sumoylation-mediated cellular pathways. We have previously reported that Ubc9 promotes tumor growth in the xenograft mouse model using breast cancer cell line MCF-7 in part through regulation of Bcl-2 expression. In this study, we show that ectopic expression of wild type Ubc9 (Ubc9-WT) promotes cell invasion and metastasis. Surprisingly, the dominant negative mutant Ubc9 (Ubc9-DN) also causes the same phenotype, indicating that the ability of Ubc9 to promote invasion and metastasis is distinct from its ability to conjugate SUMO to protein substrates. Of considerable interest, several microRNAs such as miR-224 are regulated by Ubc9. While ectopic expression of Ubc9 causes downregulation of miR-224, and suppression of Ubc9 by Ubc9-siRNAs leads to its upregulation. We further show that miR-224 can inhibit cell invasion and directly targets CDC42 and CXCR4, and that suppression of CDC42 and CXCR4 by RNAi causes inhibition of Ubc9-mediated invasion. Together, these results demonstrate a molecular link between Ubc9 and the metastasis genes such as CDC42 and CXCR4, and thus provide new insight into the mechanism by which Ubc9 promotes tumor invasion and metastasis.

Identification of a molecular recognition feature in the E1A oncoprotein that binds the SUMO conjugase UBC9 and likely interferes with polySUMOylation

“…UBC9 also regulates the response to DNA damage (Galanty et al, 2009;Morris et al, 2009;Prudden et al, 2009). Interestingly, UBC9 can promote cell invasion, metastasis and sensitivity to anticancer agents independently from its critical role in SUMOylation (Mo et al, 2004;Zhu et al, 2009), and has been suggested as a potential target for cancer therapy (Mo and Moschos, 2005).…”

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

“…Many components of the SUMO machinery are highly expressed in cancer tissues, suggesting that activated SUMOylation is linked to tumor growth (Table 1). Overexpression of the SUMO conjugating enzyme Ubc9 occurs in many types of cancer, including ovarian [63], colon and prostate cancer [64], and promotes cell invasion and metastasis [65]. Interestingly, overexpression of the SUMO proteases SENP1 and SENP5 occurs in malignant cancers, suggesting that SUMOylation needs to be tightly regulated to prevent malignant progression and cell proliferation [66,67].…”

Tumour‐suppressive microRNA‐224 inhibits cancer cell migration and invasion via targeting oncogenic TPD52 in prostate cancer

“…These results strongly suggested that miR-224 functioned as a tumour suppressor in PCa cells. Downregulation of miR-224 has also been reported in other types of human cancers, including ovarian, lung, and breast cancers, in addition to PCa [17][18][19][20][21]. Additionally, one study has shown that more aggressive PCa is associated with lower expression of miR-224 and that downregulation of miR-224 is associated with biochemical relapse [22].…”

“…Improved understanding of ncRNAs is necessary for continued progress in cancer research. MicroRNAs (miRNAs) are endogenous small ncRNA molecules (19)(20)(21)(22) bases in length) that regulate the expression of protein-coding genes by repressing translation or cleaving RNA transcripts in a sequencespecific manner [5]. A significant amount of evidence suggests that miRNAs are aberrantly expressed in many human cancers and play significant roles in the initiation, development, and metastasis of those cancers [6].…”