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Real, S. M.

Publications and source records attributed to Real, S. M..

2 recordsLinked to original sources
bioRxiv2025

Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer

Basal-like breast cancer (BLBC) is characterized by an aggressive clinical course, high genomic instability, and limited therapeutic options. The Inhibitor of Differentiation 4 (ID4) protein has been identified as a critical regulator of BLBC, where its overexpression correlates with poor prognosis. However, the mechanistic contributions of ID4 to BLBC tumorigenesis remain incompletely understood. In this study, we employed an integrative approach combining CRISPR-Cas9-mediated ID4 knockout, small-molecule inhibition, in vivo tumor modeling, and in silico transcriptional analyses to investigate the functional role of ID4 in BLBC. CRISPR-Cas9-mediated knockout of ID4 in MDA-MB-231 cells resulted in significant reductions in proliferation, colony formation, and Ki67 expression, indicating a loss of aggressive phenotypic traits. In vivo xenograft studies further revealed that ID4-silenced cells exhibited markedly delayed tumor formation and a significant reduction in metastatic potential compared to controls. Kaplan-Meier survival analysis of basal-like tumors from The Cancer Genome Atlas (TCGA) dataset demonstrated that patients with low ID4 expression had improved relapse-free survival. Gene set enrichment analysis (GSEA) of BLBC tumors stratified by ID4 expression revealed a shift toward luminal-like transcriptional programs in the ID4-low subgroup, including increased estrogen response and inflammatory signaling pathways. Furthermore, transcription factor activity analysis identified the activation of MYC, JUN, and STAT in ID4-low tumors, suggesting a transition toward a more differentiated phenotype. Finally, pharmacological inhibition of ID4 using the small-molecule degrader AGX51 effectively reduced proliferation in TNBC cells, highlighting ID4 as a potential therapeutic target. Together, these findings establish ID4 as a key driver of BLBC aggressiveness and suggest that its inhibition may represent a viable therapeutic strategy. This study provides compelling evidence supporting the development of ID4-targeted therapies for TNBC patients, with the potential to improve clinical outcomes in this challenging disease subset.

cancer biology↗
bioRxiv2024

Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control

Mitochondrial diseases, caused by mutations in either nuclear or mitochondrial DNA (mtDNA), currently have limited treatment options. For mtDNA mutations, reducing mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising therapeutic option, though current approaches face significant challenges. Previous research has shown that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, characterized by changes in DNA methylation, which does not occur or is less important when mitochondrial impairment is subtle. Building on this, we hypothesized that targeting nuclear DNA methylation could selectively compromise cells with high levels of mutant mtDNA, favor ones with lower mutant load and thereby reduce overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations--m.13513G>A and m.8344A>G--at varying heteroplasmy levels, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern to be critical for the survival of high-heteroplasmy cells but not for the low-heteroplasmy ones. Consequently, by disrupting this epigenetic programming with FDA approved DNA methylation inhibitors we managed to selectively impact high-heteroplasmy cybrids and reduce heteroplasmy. These findings were validated in both cultured cells and an in vivo xenograft model. Our study reveals a previously unrecognized role for nuclear DNA methylation in regulating cell survival in the context of mitochondrial heteroplasmy. This insight not only advances our understanding of mitochondrial-nuclear interactions but also introduces epigenetic modulation as a possible therapeutic avenue for mitochondrial diseases.

genomics↗