G-quadruplex structural dynamics at MAPK12 promoter dictates transcriptional switch to determine stemness in breast cancer.

Autor: Sengupta P; Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India., Dutta A; Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India., Suseela YV; Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bengaluru, Karnataka, 560064, India., Roychowdhury T; Department of Cancer Biology and Inflammatory Disorder, IICB, Kolkata, West Bengal, India., Banerjee N; Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India., Dutta A; Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India., Halder S; Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India., Jana K; Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India., Mukherjee G; Barasat Cancer Research and Welfare Centre, Barasat, Kolkata, West Bengal, India., Chattopadhyay S; Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, K. K. Birla Goa Campus, Goa, 403726, India., Govindaraju T; Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bengaluru, Karnataka, 560064, India. tgraju@jncasr.ac.in., Chatterjee S; Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India. subhrangsu@gmail.com.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 Jan 12; Vol. 81 (1), pp. 33. Date of Electronic Publication: 2024 Jan 12.
DOI: 10.1007/s00018-023-05046-6
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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