A RUNX-targeted gene switch-off approach modulates the BIRC5/PIF1-p21 pathway and reduces glioblastoma growth in mice.
Etsuko Yamamoto HattoriTatsuya MasudaYohei MineharuMasamitsu MikamiYukinori TeradaYasuzumi MatsuiHirohito KubotaHidemasa MatsuoMasahiro HirataTatsuki R KataokaTatsutoshi NakahataShuji IkedaSusumu MiyamotoHiroshi SugiyamaYoshiki ArakawaYasuhiko KamikuboPublished in: Communications biology (2022)
Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma.
Keyphrases
- transcription factor
- genome wide identification
- genome wide
- induced apoptosis
- copy number
- cell death
- endoplasmic reticulum stress
- oxidative stress
- signaling pathway
- dna binding
- stem cells
- gene expression
- cell proliferation
- adipose tissue
- drug delivery
- cancer therapy
- pi k akt
- resting state
- genome wide analysis
- brain injury
- deep learning