Back to Search
Start Over
Downregulation of miR-326 and its host gene β-arrestin1 induces pro-survival activity of E2F1 and promotes medulloblastoma growth
- Source :
- Molecular Oncology, Molecular Oncology, Vol 15, Iss 2, Pp 523-542 (2021)
- Publication Year :
- 2021
- Publisher :
- John Wiley and Sons Ltd, 2021.
-
Abstract
- Medulloblastoma (MB) is a malignant pediatric brain tumor, and we reveal a new regulatory molecular axis critical for MB progression. Low expression of miR‐326 and its host gene β‐arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro‐survival function. High levels of EZH2 are responsible for the presence of H3K27me3 that controls miR‐326 and ARRB1 through a bivalent domain. Restoration of miR‐326 and re‐expression of ARRB1 reverse E2F1 function into pro‐apoptotic activity.<br />Persistent mortality rates of medulloblastoma (MB) and severe side effects of the current therapies require the definition of the molecular mechanisms that contribute to tumor progression. Using cultured MB cancer stem cells and xenograft tumors generated in mice, we show that low expression of miR‐326 and its host gene β‐arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro‐survival function. Our models revealed that miR‐326 and ARRB1 are controlled by a bivalent domain, since the H3K27me3 repressive mark is found at their regulatory region together with the activation‐associated H3K4me3 mark. High levels of EZH2, a feature of MB, are responsible for the presence of H3K27me3. Ectopic expression of miR‐326 and ARRB1 provides hints into how their low levels regulate E2F1 activity. MiR‐326 targets E2F1 mRNA, thereby reducing its protein levels; ARRB1, triggering E2F1 acetylation, reverses its function into pro‐apoptotic activity. Similar to miR‐326 and ARRB1 overexpression, we also show that EZH2 inhibition restores miR‐326/ARRB1 expression, limiting E2F1 pro‐proliferative activity. Our results reveal a new regulatory molecular axis critical for MB progression.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Mice, SCID
Mice
0302 clinical medicine
Mice, Inbred NOD
E2F1
RNA, Neoplasm
ARRB1
EZH2
medulloblastoma
miR-326
Research Articles
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
beta-Arrestin 1
Oncology
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
030220 oncology & carcinogenesis
Molecular Medicine
Female
Research Article
Down-Regulation
Biology
lcsh:RC254-282
03 medical and health sciences
Downregulation and upregulation
Cancer stem cell
Genetics
medicine
Animals
Humans
Cerebellar Neoplasms
Medulloblastoma
Messenger RNA
miR‐326
medicine.disease
MicroRNAs
030104 developmental biology
HEK293 Cells
Tumor progression
Cancer research
Ectopic expression
E2F1 Transcription Factor
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Molecular Oncology, Molecular Oncology, Vol 15, Iss 2, Pp 523-542 (2021)
- Accession number :
- edsair.doi.dedup.....52945c7d4b7b32d0c39e800460cb4da1