SHMT2 promotes papillary thyroid cancer metastasis through epigenetic activation of AKT signaling.
Cell Death Dis
; 15(1): 87, 2024 01 25.
Article
in En
| MEDLINE
| ID: mdl-38272883
ABSTRACT
Cancer cells alter their metabolism and epigenetics to support cancer progression. However, very few modulators connecting metabolism and epigenetics have been uncovered. Here, we reveal that serine hydroxymethyltransferase-2 (SHMT2) generates S-adenosylmethionine (SAM) to epigenetically repress phosphatase and tensin homolog (PTEN), leading to papillary thyroid cancer (PTC) metastasis depending on activation of AKT signaling. SHMT2 is elevated in PTC, and is associated with poor prognosis. Overexpressed SHMT2 promotes PTC metastasis both in vitro and in vivo. Proteomic enrichment analysis shows that AKT signaling is activated, and is positively associated with SHMT2 in PTC specimens. Blocking AKT activation eliminates the effects of SHMT2 on promoting PTC metastasis. Furthermore, SHMT2 expression is negatively associated with PTEN, a negative AKT regulator, in PTC specimens. Mechanistically, SHMT2 catalyzes serine metabolism and produces activated one-carbon units that can generate SAM for the methylation of CpG islands in PTEN promoter for PTEN suppression and following AKT activation. Importantly, interference with PTEN expression affects SHMT2 function by promoting AKT signaling activation and PTC metastasis. Collectively, our research demonstrates that SHMT2 connects metabolic reprogramming and epigenetics, contributing to the poor progression of PTC.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thyroid Neoplasms
/
Proto-Oncogene Proteins c-akt
Limits:
Humans
Language:
En
Journal:
Cell Death Dis
Year:
2024
Document type:
Article
Affiliation country: