LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination.
Humans
Bone Neoplasms
/ pathology
Cell Line, Tumor
Cell Proliferation
/ genetics
Gene Expression Regulation, Neoplastic
Osteosarcoma
/ pathology
RNA, Long Noncoding
/ genetics
Signal Transduction
/ genetics
Tripartite Motif-Containing Protein 28
/ genetics
Tuberous Sclerosis Complex 2 Protein
/ metabolism
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
Dec 2022
Dec 2022
Historique:
received:
30
06
2022
accepted:
28
10
2022
revised:
26
10
2022
pubmed:
9
11
2022
medline:
15
12
2022
entrez:
8
11
2022
Statut:
ppublish
Résumé
Osteosarcoma, the most common pediatric bone tumor, is an aggressive heterogeneous malignancy defined by complex chromosomal aberrations. Overall survival rates remain at ~70%, but patients with chemoresistant or metastatic disease have extremely poor outcomes of <30%. A subgroup of tumors harbor amplification of chromosome 8q24.2 and increased expression of the oncogenic long noncoding RNA (lncRNA) Plasmacytoma Variant Translocation-1 (PVT-1), which is associated with an extremely poor clinical prognosis. This study demonstrates that PVT-1 is critical for osteosarcoma tumor-initiation potential. Chromatin Hybridization by RNA Purification analysis identified Tripartite-Motif Containing Family 28 (TRIM28) as a novel PVT-1 binding partner. Mechanistically, co-immunoprecipitation studies showed the PVT-1/TRIM28 complex binds and increases SUMOylation of phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34), which leads to enhanced ubiquitination and degradation of tumor suppressor complex 2 (TSC2), thus contributing to increased self-renewal and stem cell phenotypes. Furthermore, we identified that osteosarcoma cells with increased PVT-1 have enhanced sensitivity to the SUMOylation inhibitor, TAK-981. Altogether, this study elucidated a role for PVT-1 in the enhancement of cancer stem-like behaviors, including migration and invasion, in osteosarcoma, and identified the novel PVT-1/TRIM28 axis signaling cascade as a potential therapeutic target for osteosarcoma treatment.
Identifiants
pubmed: 36348010
doi: 10.1038/s41388-022-02538-w
pii: 10.1038/s41388-022-02538-w
doi:
Substances chimiques
RNA, Long Noncoding
0
TRIM28 protein, human
EC 2.3.2.27
Tripartite Motif-Containing Protein 28
EC 2.3.2.27
TSC2 protein, human
0
Tuberous Sclerosis Complex 2 Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5373-5384Subventions
Organisme : Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
ID : RP170005
Organisme : Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
ID : RP180672
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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