MTA3 Represses Cancer Stemness by Targeting the SOX2OT/SOX2 Axis

Abstract

SummaryCancer cell stemness (CCS) plays critical roles in both malignancy maintenance and metastasis, yet the underlying molecular mechanisms are far from complete. Although the importance of SOX2 in cancer development and CCS are well recognized, the role of MTA3 in these processes is unknown. In this study, we used esophageal squamous cell carcinoma (ESCC) as a model system to demonstrate that MTA3 can repress both CCS and metastasis in vitro and in vivo. Mechanistically, by forming a repressive complex with GATA3, MTA3 downregulates SOX2OT, subsequently suppresses the SOX2OT/SOX2 axis, and ultimately represses CCS and metastasis. More importantly, MTA3low/SOX2high is associated with poor prognosis and could serve as an independent prognostic factor. These findings altogether indicate that MTA3/SOX2OT/SOX2 axis plays an indispensable role in CCS. Therefore, this axis could be potentially used in cancer stratification and serves as a therapeutic target.

LncRNA SOX2‐OT regulates AKT/ERK and SOX2/GLI‐1 expression, hinders therapy, and worsens clinical prognosis in malignant lung diseases

“…In the case of lung cancer, some studies have previously reported that SOX2‐OT overexpression is associated with worse clinical outcomes, suggesting a role as an independent prognostic factor, though the data remain inconclusive thus far [22,32]. The MTA3/SOX2‐OT/SOX2 axis has been involved as a prognostic factor for poor clinical outcomes in esophageal squamous cell carcinoma patients [40]. Results from our study confirm that overexpressed LncRNA SOX2‐OT is involved in the control of SOX2‐OT/SOX2/GLI‐1 axis expression, as probable key archetypes, including as ‘scaffold’ to RNA‐binding protein (RBP) [65], and ceRNA function reported on SOX2‐targeting miR200c [15], or hypothetically involved in ceRNA activity on miR326 [66], or miR218 [67] whose miRNAs are involved in GLI‐1‐targeting.…”

“…However, scarce experimental evidence allows us to explain the expression of the SOX2-OT/SOX2 axis in cancer, which has been recently reported to be genetic/epigenetically regulated through MTA3 and GATA3, probably in a NurD (chromatin remodeling complex) interaction, affecting cancer stemness and metastasis. This would propose the MTA3/SOX2-OT/SOX2 axis as a potential cancer stratification molecular-marker, and therapeutic targets in human esophageal squamous cell carcinomas[40]. Additionally, another LncRNA/mRNA binomial axis (GLI1-AS/GLI-1), has been reported to be epigenetically regulated (enriched histone H3K27me3) at bidirectional gene promoter sequences, involved in tumor cellular proliferation and in vivo xenograft tumor growth[34].Interestingly, resistance mechanisms to oncological drugs based on drug-efflux, cell apoptosis, autophagy, and cancer cell stemness, as well as, mutations in TK-receptors (e.g.…”

Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration

“…Immunoblotting was performed as described previously ( Gan et al, 2016 ; Du et al, 2019 ; Xiong et al, 2020 ; Wang et al, 2021b ). Briefly, total proteins were extracted from the breast cancer cells or exosomes on ice with radioimmunoprecipitation assay (RIPA) cell lysis buffer supplemented with protease inhibitors.…”

MicroRNAs regulating SOX2 in cancer progression and therapy response

“…MTA3 can function as upstream regulator of SOX2, suppressing its expression and preventing cancer metastasis (Ref. 81). In contrast, transmembrane 4 L six family member 1 (TM4SF1) induces SOX2 expression via upregulating Wnt expression, leading to metastasis and epithelial-to-mesenchymal transition (EMT) stimulation in colorectal tumour (Ref.…”