LINC00963-FOSB-mediated transcription activation of UBE3C enhances radioresistance of breast cancer cells by inducing ubiquitination-dependent protein degradation of TP73

Abstract

Background The ubiquitin protein ligase E3C (UBE3C) has been reported to play an oncogenic role in breast cancer (BRCA). This work further investigates the effect of UBE3C on the radioresistance of BRCA cells. Methods Molecules linking to radioresistance in BRCA were identified by analyzing two GEO datasets, GSE31863 and GSE101920. UBE3C overexpression or knockdown was induced in parental or radioresistant BRCA cells, followed by irradiation treatment. The malignant properties of cells in vitro, and the growth and metastatic activity of cells in nude mice, were analyzed. Downstream target proteins, as well as upstream transcriptional regulators of UBE3C, were predicted by bioinformatics tools. Molecular interactions were confirmed by immunoprecipitation and immunofluorescence assays. Furthermore, artificial alterations of TP73 and FOSB were induced in the BRCA cells for functional rescue assays. Results According to bioinformatics analyses, UBE3C expression was linked to radioresistance in BRCA. UBE3C knockdown in radioresistant BRCA cells reduced while its overexpression in parental BRCA cells increased the radioresistance of cells in vitro and in vivo. UBE3C, which induced ubiquitination-dependent protein degradation of TP73, was transcriptionally activated by FOSB. The radioresistance of cancer cells was blocked by TP73 overexpression or FOSB knockdown. Additionally, LINC00963 was found to be responsible for the recruitment of FOSB to the UBE3C promoter for transcription activation. Conclusion This work demonstrates that LINC00963 induces nuclear translocation of FOSB and the consequent transcription activation of UBE3C, which enhances radioresistance of BRCA cells by inducing ubiquitination-dependent protein degradation of TP73. Graphical Abstract

LNC01089-LINC00963/miR-1244-5p/IGF1 ceRNA axis might regulate FOXO signaling pathway in breast cancer patients: a biomarker discovery investigation

“…An examination into the mechanism of action found that LINC00963 can interact with microRNA-625 (miR-625). LINC00963 inhibited the inhibitory impact of miR-625 on high mobility group AT-hook 1 (HMGA1) in breast cancer cells by acting as a ceRNA for miR-625 (Wu et al, 2020) (Wang et al, 2023). Our results about the gene expression pattern of LINC00963 validated our bioinformatics analyses, but it was different from previous investigations.…”

The Mechanism of Ubiquitination or Deubiquitination Modifications in Regulating Solid Tumor Radiosensitivity

“…An analysis of the Gene Expression Omnibus (GEO) databases GSE31863 and GSE101920 revealed the upregulation of the E3 ligase UBE3C in breast cancer tissue samples, and its elevation correlated with adverse radiological responses. Correlation experiments were conducted on molecules upstream and downstream of UBE3C; LINC00963 activates UBE3C transcription by facilitating the nuclear translocation of FOSB, and UBE3C catalyzes the ubiquitination degradation of the tumor suppressor TP73, thus enhancing the radioresistance of tumor cells [62]. Similarly, ubiquitinconjugating enzyme E2 C (UBE2C) also plays a role in regulating the radiosensitivity of breast cancer cells, though the exact mechanism requires further exploration [113].…”