SNAI2 cooperates with MEK1/2 and HDACs to suppress BIM- and BMF-dependent apoptosis in TERT promoter mutant cancers
Amol Tandon, Josh Lewis Stern
Abstract
Cancers with TERT promoter mutations (TPM) display elevated RAS pathway signaling and mesenchymal traits, and associate with lower patient survival rates. We examined whether RAS pathway signaling in TPM cancers cooperates with mesenchymal features to drive resistance to apoptosis. We observed that RAS pathway signaling in TPM cancers inhibited apoptosis by downregulating the pro-apoptotic protein BIM. By using inhibitors of MEK1/2 kinases, we rescued the ability of TPM cancer cells to undergo apoptosis, which may have implications for targeted therapies.
Introduction
Genetic alterations in tumors play a crucial role in determining patient outcomes, and the development of personalized interventions is emerging as a promising therapeutic approach [1,2]. Coding mutations in genes such as MYC, BRAF, TP53, and PIK3CA are well known to drive a large subset of cancers [3–6].
Materials and method
Cell culture
TERT promoter mutant (TPM) cell lines used in the study were derived from Breast cancer (MDA-MB-231), hepatocellular carcinoma (SNU-475, SNU-423), melanoma (A101D (CRL-7898), UACC-257), Bladder cancer (SCaBER) and central nervous system (U87, LN229 (CRL-2611), SKNSH and DAOY (HTB-186)). Cells were maintained as an adherent culture in DMEM media (Cytiva, SH30022.02) supplemented with glutamine (Cytiva, SH30590.01), 10% fetal bovine serum (FBS) (Corning 35–010-CV) and 1% Penicillin/Streptomycin (Cytiva SV30010), sodium pyruvate (Cytiva, SH30239.01).
Results
MEK1/2 inhibition in TPM cancers promotes BIM rescue leading to apoptosis
Cancer cells frequently employ mechanisms that enable escape from apoptosis, including activation of RAS signaling [21,22]. TERT promoter mutant (TPM) cancer cells are characterized by gene expression signatures matching RAS pathway driven states, although many of these are not explained by mutations known to activate the RAS pathway [14]. We first validated RAS pathway activation in a panel of TPM cancer cell lines by determining the level of phosphorylated ERK1 and ERK2 (pERK), aiming to document the frequent association of TPMs with elevated RAS signaling.
Discussion
Although cancers with TERT promoter mutations occur across a seemingly disparate subset of cancer types, they are now known to be common in those that display RAS pathway expression profiles and mesenchymal traits [14]. Previous studies in selected cancer types have shown that reliance on RAS signaling and mesenchymal programs lead to specific therapeutic vulnerabilities [33,34].
Acknowledgments
C. Ryan Miller and Erin Smithberger, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham; James Costello, University of Colorado, Anschutz.
Citation: Tandon A, Stern JL (2025) SNAI2 cooperates with MEK1/2 and HDACs to suppress BIM- and BMF-dependent apoptosis in TERT promoter mutant cancers. PLoS One 20(6): e0322961. https://doi.org/10.1371/journal.pone.0322961
Editor: Kai Huang, University of Pennsylvania, UNITED STATES OF AMERICA
Received: October 24, 2024; Accepted: March 31, 2025; Published: June 25, 2025
Copyright: © 2025 Tandon, Stern. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All raw data generated in the study can be accessed in a Figshare repository with the following DOI: (10.6084/m9.figshare.28103435).
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
