Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
G-quadruplex structural dynamics at MAPK12 promoter dictates transcriptional switch to determine stemness in breast cancer
Ist Teil von
Cellular and molecular life sciences : CMLS, 2024-12, Vol.81 (1), p.33-33, Article 33
Ort / Verlag
Cham: Springer International Publishing
Erscheinungsjahr
2024
Link zum Volltext
Quelle
SpringerLink
Beschreibungen/Notizen
P38γ (MAPK12) is predominantly expressed in triple negative breast cancer cells (TNBC) and induces stem cell (CSC) expansion resulting in decreased survival of the patients due to metastasis. Abundance of G-rich sequences at
MAPK12
promoter implied the functional probability to reverse tumorigenesis, though the formation of G-Quadruplex (G4) structures at
MAPK12
promoter is elusive. Here, we identified two evolutionary consensus adjacent G4 motifs upstream of the
MAPK12
promoter, forming parallel G4 structures. They exist in an equilibria between G4 and duplex, regulated by the binding turnover of Sp1 and Nucleolin that bind to these G4 motifs and regulate
MAPK12
transcriptional homeostasis. To underscore the gene-regulatory functions of G4 motifs, we employed CRISPR-Cas9 system to eliminate G4s from TNBC cells and synthesized a naphthalene diimide (NDI) derivative (TGS24) which shows high-affinity binding to
MAPK12-G4
and inhibits
MAPK12
transcription. Deletion of G4 motifs and NDI compound interfere with the recruitment of the transcription factors, inhibiting MAPK12 expression in cancer cells. The molecular basis of NDI-induced G4 transcriptional regulation was analysed by RNA-seq analyses, which revealed that
MAPK12-G4
inhibits oncogenic RAS transformation and trans-activation of
NANOG
.
MAPK12-G4
also reduces CD44
High
/CD24
Low
population in TNBC cells and downregulates internal stem cell markers, arresting the stemness properties of cancer cells.