Post-translational modification of SOX family proteins: Key biochemical targets in cancer?

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.

Articular Chondrocyte Phenotype Regulation through the Cytoskeleton and the Signaling Processes That Originate from or Converge on the Cytoskeleton: Towards a Novel Understanding of the Intersection between Actin Dynamics and Chondrogenic Function

“…Additionally, the TGF-β-mediated SOX9 phosphorylation and stabilization in CHs is dependent on p38 activity and also Smad2/3 at S211 [306] (Figure 12C). [301]. Details are specified in the text.…”

“…This was interpreted that a 3D alginate culture increases the transcriptional activity of SOX9 in a PKA-dependent fashion. On a side note, human SOX9 has three phosphorylation sites, namely, S62, S181, and S211, for PKA [ 301 ], and a study [ 302 ] demonstrated the phosphorylation by PKA at S64 and S181, whereas [ 72 ] then demonstrated that phosphorylation specifically of S181 was necessary for 3D alginate-induced actin depolymerization to enhance SOX9 function. The latter study also demonstrated that the phosphorylation site S64 or mutant phosphorylation sites, such as S181A or 181A, were not involved in 3D alginate-induced effects on SOX9 activity.…”

Sorting Sox: Diverse Roles for Sox Transcription Factors During Neural Crest and Craniofacial Development

“…SOX proteins undergo a number of post-translational modifications, including: acetylation, methylation, phosphorylation, SUMOylation, and ubiquitination (Williams et al, 2019). Several of these modifications have been shown to impact neural crest development (Huang et al, 2000;LaBonne, 2005, 2007;Sakai et al, 2006;Lee et al, 2012;Liu et al, 2013).…”

“…It is likely, however, that this relationship is more complex and context dependent as observed with other transcription factors (Long et al, 2004;Taylor and LaBonne, 2005;Rosonina et al, 2017). Finally, SoxE factors also have putative acetylation and methylation sites (Williams et al, 2019); however, functional roles for these modifications during neural crest development remains largely unknown. One study demonstrated that Sox9 is acetylated by Tip60; however, the acetylation state did not impact the ability of Sox9 to activate Col2a1 expression (Hattori et al, 2008).…”

Posttranslational Modification of Sox11 Regulates RGC Survival and Axon Regeneration

“…These data extend our previous study that deSUMOlyated Sox11 translocates into the nucleus to more potently regulate RGC differentiation ( Chang et al, 2017 ). SUMO conjugation acts to regulate many transcription factors, including other Sox family proteins ( Williams et al, 2020 ). Ubiquitin-conjugating enzyme 9 (Ubc9) can interact with Sox4 in the nucleus and repress Sox4’s transcriptional activity, even without its SUMO-1 conjugating capability ( Pan et al, 2006 ).…”