Interplay between acetylation and ubiquitination controls PSAT1 protein stability in lung adenocarcinoma

Abstract

Serine is essential to maintain maximal growth and proliferation of cancer cells by providing adequate intermediate metabolites and energy. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in de novo serine synthesis. However, little is known about the mechanisms underlying PSAT1 degradation. We found that acetylation was the switch that regulated the degradation of PSAT1 in lung adenocarcinoma (LUAD). Deacetylation of PSAT1 on Lys51 by histone deacetylase 7 (HDAC7) enhanced the interaction between PSAT1 and the deubiquitinase ubiquitin-specific processing protease 14 (USP14), leading to the deubiquitination and stabilization of PSAT1; while acetylation of PSAT1 promoted its interaction with the E3 ligase ubiquitination factor E4B (UBE4B), leading to proteasomal degradation. Acetylation of PSAT1 on Lys51 regulated serine metabolism and tumor proliferation in LUAD. Thus, acetylation and ubiquitination cooperatively regulated the protein homeostasis of PSAT1. In conclusion, our study reveals a key regulatory mechanism for maintaining PSAT1 protein homeostasis in LUAD. Acetylation and ubiquitination cooperatively regulate the protein homeostasis of PSAT1 and contribute to serine synthesis and tumorigenesis of lung adenocarcinoma.