Interplay Between Acetylation and Ubiquitination Controls PSAT1 Protein Stability in Lung Adenocarcinoma

Overview

Journal Commun Biol

Specialty Biology

Date 2024 Oct 21

PMID 39433916

Authors

Yuhan Liu

Wenze Xun

Tao Zhao

Menglin Huang

Longhua Sun

Guilan Wen

Xiuhua Kang

Jianbin Wang

Tianyu Han

Affiliations

Soon will be listed here.

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.

References

Wei Y, Zhou F, Zhou H, Huang J, Yu D, Wu G . Endothelial progenitor cells contribute to neovascularization of non-small cell lung cancer via histone deacetylase 7-mediated cytoskeleton regulation and angiogenic genes transcription. Int J Cancer. 2018; 143(3):657-667. DOI: 10.1002/ijc.31349. View

Yang Y, Wu J, Cai J, He Z, Yuan J, Zhu X . PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells. Int J Cancer. 2014; 136(4):E39-50. DOI: 10.1002/ijc.29150. View

Sun L, Suo C, Li S, Zhang H, Gao P . Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect. Biochim Biophys Acta Rev Cancer. 2018; 1870(1):51-66. DOI: 10.1016/j.bbcan.2018.06.005. View

Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza A . Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 2012; 336(6084):1040-4. PMC: 3526189. DOI: 10.1126/science.1218595. View

McClurg U, Robson C . Deubiquitinating enzymes as oncotargets. Oncotarget. 2015; 6(12):9657-68. PMC: 4496387. DOI: 10.18632/oncotarget.3922. View

Witt O, Deubzer H, Milde T, Oehme I . HDAC family: What are the cancer relevant targets?. Cancer Lett. 2008; 277(1):8-21. DOI: 10.1016/j.canlet.2008.08.016. View

Shahbazian M, Grunstein M . Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem. 2007; 76:75-100. DOI: 10.1146/annurev.biochem.76.052705.162114. View

Zhou X, Tian C, Cao Y, Zhao M, Wang K . The role of serine metabolism in lung cancer: From oncogenesis to tumor treatment. Front Genet. 2023; 13:1084609. PMC: 9868472. DOI: 10.3389/fgene.2022.1084609. View

Feng M, Cui H, Tu W, Li L, Gao Y, Chen L . An integrated pan-cancer analysis of PSAT1: A potential biomarker for survival and immunotherapy. Front Genet. 2022; 13:975381. PMC: 9465327. DOI: 10.3389/fgene.2022.975381. View

10.

DeBerardinis R . Serine metabolism: some tumors take the road less traveled. Cell Metab. 2011; 14(3):285-6. PMC: 3172581. DOI: 10.1016/j.cmet.2011.08.004. View

11.

Wang H, Cui L, Li D, Fan M, Liu Z, Liu C . Overexpression of PSAT1 regulated by G9A sustains cell proliferation in colorectal cancer. Signal Transduct Target Ther. 2020; 5(1):47. PMC: 7162942. DOI: 10.1038/s41392-020-0147-5. View

12.

Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G . Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014; 39(4):191-8. PMC: 3989988. DOI: 10.1016/j.tibs.2014.02.004. View

13.

Ye J, Mancuso A, Tong X, Ward P, Fan J, Rabinowitz J . Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci U S A. 2012; 109(18):6904-9. PMC: 3345000. DOI: 10.1073/pnas.1204176109. View

14.

Maddocks O, Berkers C, Mason S, Zheng L, Blyth K, Gottlieb E . Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature. 2012; 493(7433):542-6. PMC: 6485472. DOI: 10.1038/nature11743. View

15.

Zhao C, Gong J, Bai Y, Yin T, Zhou M, Pan S . A self-amplifying USP14-TAZ loop drives the progression and liver metastasis of pancreatic ductal adenocarcinoma. Cell Death Differ. 2022; 30(1):1-15. PMC: 9883464. DOI: 10.1038/s41418-022-01040-w. View

16.

Metcalf S, Dougherty S, Kruer T, Hasan N, Biyik-Sit R, Reynolds L . Selective loss of phosphoserine aminotransferase 1 (PSAT1) suppresses migration, invasion, and experimental metastasis in triple negative breast cancer. Clin Exp Metastasis. 2019; 37(1):187-197. DOI: 10.1007/s10585-019-10000-7. View

17.

Newman A, Maddocks O . Serine and Functional Metabolites in Cancer. Trends Cell Biol. 2017; 27(9):645-657. DOI: 10.1016/j.tcb.2017.05.001. View

18.

Rose M, Kostyanovskaya E, Huang R . Pharmacogenomics of cisplatin sensitivity in non-small cell lung cancer. Genomics Proteomics Bioinformatics. 2014; 12(5):198-209. PMC: 4411417. DOI: 10.1016/j.gpb.2014.10.003. View

19.

Chau V, Tobias J, Bachmair A, Marriott D, Ecker D, Gonda D . A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science. 1989; 243(4898):1576-83. DOI: 10.1126/science.2538923. View

20.

Lee B, Lu Y, Prado M, Shi Y, Tian G, Sun S . USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites. Nature. 2016; 532(7599):398-401. PMC: 4844788. DOI: 10.1038/nature17433. View