Post-translational Modification of SOX Family Proteins: Key Biochemical Targets in Cancer?

Overview

Journal Semin Cancer Biol

Specialty Oncology

Date 2019 Sep 21

PMID 31539559

Citations 20

Authors

Charles A C Williams

Abdenour Soufi

Steven M Pollard

Affiliations

Soon will be listed here.

Abstract

Sox proteins are a family of lineage-associated transcription factors. They regulate expression of genes involved in control of self-renewal and multipotency in both developmental and adult stem cells. Overexpression of Sox proteins is frequently observed in many different human cancers. Despite their importance as therapeutic targets, Sox proteins are difficult to 'drug' using structure-based design. However, Sox protein localisation, activity and interaction partners are regulated by a plethora of post-translational modifications (PTMs), such as: phosphorylation, acetylation, sumoylation, methylation, and ubiquitylation. Here we review the various reported post-translational modifications of Sox proteins and their potential functional importance in guiding cell fate processes. The enzymes that regulate these PTMs could be useful targets for anti-cancer drug discovery.

Citing Articles

The molecular pathogenesis of SOX2 in prostate cancer.

Liu S, Yu H, Zhao Z Discov Oncol. 2025; 16(1):215.

PMID: 39976818 PMC: 11842661. DOI: 10.1007/s12672-025-01972-y.

Disruption of Sex-Linked Causes ZW Female-to-Male Sex Reversal in the Japanese Frog .

Miura I, Hasegawa Y, Ito M, Ezaz T, Ogata M Biomolecules. 2025; 14(12.

PMID: 39766273 PMC: 11673724. DOI: 10.3390/biom14121566.

Construction and validation of a novel prognostic model with palmitoylation-related genes for glioblastoma.

Qin G, Pang G, Wu S, Bi S, Lan S, Tang X Transl Cancer Res. 2024; 13(11):6117-6135.

PMID: 39697698 PMC: 11651772. DOI: 10.21037/tcr-24-787.

Exploring the reciprocity between pioneer factors and development.

Freund M, Harrison M, Torres-Zelada E Development. 2024; 151(13).

PMID: 38958075 PMC: 11266817. DOI: 10.1242/dev.201921.

DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2.

Bjarnason S, McIvor J, Prestel A, Demeny K, Bullerjahn J, Kragelund B Nat Commun. 2024; 15(1):1445.

PMID: 38365983 PMC: 10873366. DOI: 10.1038/s41467-024-45847-2.

References

Hansen B, Gupta R, Baldus L, Lyon D, Narita T, Lammers M . Analysis of human acetylation stoichiometry defines mechanistic constraints on protein regulation. Nat Commun. 2019; 10(1):1055. PMC: 6401094. DOI: 10.1038/s41467-019-09024-0. View

Shiromizu T, Adachi J, Watanabe S, Murakami T, Kuga T, Muraoka S . Identification of missing proteins in the neXtProt database and unregistered phosphopeptides in the PhosphoSitePlus database as part of the Chromosome-centric Human Proteome Project. J Proteome Res. 2013; 12(6):2414-21. DOI: 10.1021/pr300825v. View

Deluz C, Friman E, Strebinger D, Benke A, Raccaud M, Callegari A . A role for mitotic bookmarking of SOX2 in pluripotency and differentiation. Genes Dev. 2016; 30(22):2538-2550. PMC: 5159668. DOI: 10.1101/gad.289256.116. View

Caravaca J, Donahue G, Becker J, He X, Vinson C, Zaret K . Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Genes Dev. 2013; 27(3):251-60. PMC: 3576511. DOI: 10.1101/gad.206458.112. View

Wang J, Zhang Y, Hou J, Qian X, Zhang H, Zhang Z . Ube2s regulates Sox2 stability and mouse ES cell maintenance. Cell Death Differ. 2015; 23(3):393-404. PMC: 5072435. DOI: 10.1038/cdd.2015.106. View

Guo Y, Manteiga J, Henninger J, Sabari B, DallAgnese A, Hannett N . Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature. 2019; 572(7770):543-548. PMC: 6706314. DOI: 10.1038/s41586-019-1464-0. View

Ferguson F, Gray N . Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018; 17(5):353-377. DOI: 10.1038/nrd.2018.21. View

Sinclair A, Berta P, Palmer M, Hawkins J, GRIFFITHS B, Smith M . A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990; 346(6281):240-4. DOI: 10.1038/346240a0. View

Ito M . Function and molecular evolution of mammalian Sox15, a singleton in the SoxG group of transcription factors. Int J Biochem Cell Biol. 2009; 42(3):449-52. DOI: 10.1016/j.biocel.2009.10.023. View

10.

Wang Z, Kang L, Zhang H, Huang Y, Fang L, Li M . AKT drives SOX2 overexpression and cancer cell stemness in esophageal cancer by protecting SOX2 from UBR5-mediated degradation. Oncogene. 2019; 38(26):5250-5264. DOI: 10.1038/s41388-019-0790-x. View

11.

Huang W, Zhou X, Lefebvre V, de Crombrugghe B . Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. Mol Cell Biol. 2000; 20(11):4149-58. PMC: 85784. DOI: 10.1128/MCB.20.11.4149-4158.2000. View

12.

Bergel M, Herrera J, Thatcher B, Vassilev A, Nakatani Y, Martin B . Acetylation of novel sites in the nucleosomal binding domain of chromosomal protein HMG-14 by p300 alters its interaction with nucleosomes. J Biol Chem. 2001; 275(15):11514-20. DOI: 10.1074/jbc.275.15.11514. View

13.

Osaki E, Nishina Y, Inazawa J, Copeland N, Gilbert D, Jenkins N . Identification of a novel Sry-related gene and its germ cell-specific expression. Nucleic Acids Res. 1999; 27(12):2503-10. PMC: 148454. DOI: 10.1093/nar/27.12.2503. View

14.

Sabari B, DallAgnese A, Boija A, Klein I, Coffey E, Shrinivas K . Coactivator condensation at super-enhancers links phase separation and gene control. Science. 2018; 361(6400). PMC: 6092193. DOI: 10.1126/science.aar3958. View

15.

Soufi A, Dalton S . Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming. Development. 2016; 143(23):4301-4311. PMC: 5201050. DOI: 10.1242/dev.142075. View

16.

Kamachi Y, Kondoh H . Sox proteins: regulators of cell fate specification and differentiation. Development. 2013; 140(20):4129-44. DOI: 10.1242/dev.091793. View

17.

Malki S, Boizet-Bonhoure B, Poulat F . Shuttling of SOX proteins. Int J Biochem Cell Biol. 2009; 42(3):411-6. DOI: 10.1016/j.biocel.2009.09.020. View

18.

Mertins P, Mani D, Ruggles K, Gillette M, Clauser K, Wang P . Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016; 534(7605):55-62. PMC: 5102256. DOI: 10.1038/nature18003. View

19.

Remenyi A, Lins K, Nissen L, Reinbold R, Scholer H, Wilmanns M . Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers. Genes Dev. 2003; 17(16):2048-59. PMC: 196258. DOI: 10.1101/gad.269303. View

20.

Larsen S, Sylvestersen K, Mund A, Lyon D, Mullari M, Madsen M . Proteome-wide analysis of arginine monomethylation reveals widespread occurrence in human cells. Sci Signal. 2016; 9(443):rs9. DOI: 10.1126/scisignal.aaf7329. View