GD3 Synthase Drives Resistance to p53-Induced Apoptosis in Breast Cancer by Modulating Mitochondrial Function

Authors

Vivek Anand
Fouad El-Dana
Natalia Baran
Jenny Borgman
Zheng Yin
Hong Zhao
Stephen T Wong
Michael Andreeff
V Lokesh Battula

Language

English

Publication Date

8-1-2025

Journal

Oncogene

DOI

10.1038/s41388-025-03432-x

PMID

40382494

PMCID

PMC12277176

PubMedCentral® Posted Date

5-17-2025

PubMedCentral® Full Text Version

Post-print

Abstract

TP53 mutations are common in breast cancer (BC) and are associated with poor prognosis. GD3 synthase (GD3S/ST8SIA1), a gene associated with breast cancer stem cells, is upregulated in tumors with p53 mutations. However, the functional relationship between GD3S and p53 is unknown. Here, we show that GD3S levels are highest in breast tumors with specific p53 mutations. Functional studies revealed that wild-type (WT) p53 inhibits GD3S expression, whereas mutation in p53 enhances GD3S expression by upregulating GD3S promoter activity. Moreover, we found that GD3S inhibits wild-type p53-induced apoptosis in BC cells, while BC cells harboring gain-of-function p53 mutations are dependent on GD3S for their growth. Mechanistic insights indicate that GD3S strengthens mitochondrial function by regulating their oxygen consumption rate and membrane polarity. Our findings demonstrate that specific GOF p53 mutations rely on GD3S to exert their tumor-promoting effects and that GD3S is a novel anti-apoptotic factor in BC cells. Stabilizing WT p53 and reducing mutant p53 levels downregulates GD3S expression, thereby augmenting apoptosis. GD3S overexpression counteracts the cell death triggered by WT p53 stabilization in BC cells, as well as that triggered by p53 knockdown in cells with specific GOF p53 mutations, which suggests that GD3S helps confer apoptosis resistance.

Keywords

Humans, Tumor Suppressor Protein p53, Breast Neoplasms, Apoptosis, Mitochondria, Female, Sialyltransferases, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Mutation, Animals, Breast cancer, Mechanisms of disease

Published Open-Access

yes

Recommended Citation

Anand, Vivek; El-Dana, Fouad; Baran, Natalia; et al., "GD3 Synthase Drives Resistance to p53-Induced Apoptosis in Breast Cancer by Modulating Mitochondrial Function" (2025). Faculty, Staff and Student Publications. 5271.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5271