UBE2D3 regulated by WTAP-mediated m6A modification inhibits temozolomide chemosensitivity in glioblastoma

Jul 31, 2024Naunyn-Schmiedeberg's archives of pharmacology

UBE2D3 controlled by WTAP-related RNA modification reduces glioblastoma sensitivity to temozolomide chemotherapy

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

UBE2D3 levels were found to be elevated in glioblastoma (GBM) tissues compared to normal brain tissues.

UBE2D3 is associated with the DNA repair signaling pathway in glioblastoma.
Reducing UBE2D3 expression enhances the effectiveness of temozolomide (TMZ) treatment, leading to increased apoptosis and DNA damage in GBM cells.
Overexpression of UBE2D3 counteracts the effects of TMZ, promoting cell viability and tumor growth.
WTAP is involved in the regulation of UBE2D3 expression through mA modification, which is dependent on IGF2BP1.
The WTAP-IGF2BP1 axis plays a role in the stability of UBE2D3, influencing tumor malignancy and sensitivity to TMZ.

AI simplified

To explore how the ubiquitin-conjugating enzyme E2D3 (UBE2D3) influences temozolomide (TMZ) resistance in glioblastoma (GBM), and to clarify the association between UBE2D3 and WTAP. The UBE2D3 protein expression in GBM tissues were detected using immunohistochemistry (IHC) through tissue microarrays. The potential pathways of UBE2D3 in TCGA-GBM were predicted via Gene Set Enrichment Analysis (GSEA). To investigate UBE2D3's role in TMZ resistance, GBM cells were transduced with UBE2D3 shRNA or overexpression lentivirus, followed by assessments of CCK-8, flow cytometry, comet assay, and western blot analysis. Furthermore, a subcutaneous tumor model was established in nude mice using U87 cells transduced with interfering lentivirus to observe tumor growth and assess cell apoptosis using TUNEL staining. Mechanically, mA content analysis, mA methylated RNA immunoprecipitation quantitative PCR, reporter gene assay, mRNA stability measurements, RNA immunoprecipitation, quantitative Real-Time PCR, and Western blot assays were carried out to verify the role of WTAP/IGF2BP1 in regulating UBE2D3 expression. UBE2D3 exhibited elevated expression levels in GBM tissues compared with normal brain tissues and was associated with the DNA repair signaling pathway. In both in vitro and in vivo studies, it was demonstrated that TMZ treatment combined with reduced UBE2D3 expression further suppressed U87 cell viability and tumor growth, with a notable increase in apoptosis rate and DNA damage. Conversely, the overexpression of UBE2D3 had the opposite impact. Furthermore, our findings revealed that WTAP promotes the mA modification of UBE2D3 via an IGF2BP1-dependent mechanism. The WTAP-IGF2BP1 axis regulates UBE2D3 stability in an mA-dependent manner, influencing tumor malignancy and TMZ chemosensitivity in GBM via the DNA repair signaling pathway. 6 6 6 6

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text (HTML) ↗

UBE2D3 regulated by WTAP-mediated m6A modification inhibits temozolomide chemosensitivity in glioblastoma

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief