Acetylation stabilizes stathmin1 and promotes its activity contributing to gallbladder cancer metastasis

Abstract

Gallbladder cancer is the most common biliary tract malignant tumor with highly metastatic characters and poor prognosis. However, the underlying mechanism remains unclear. Stathmin1 is ubiquitous phosphoprotein, regulating microtubule stabilization. We identified the acetylation of stahtmin1 at lysine 9 (K9) in gallbladder cancer. K9 acetylation of stathmin1 was reversely regulated by the acetyltransferase PCAF and the deacetylases sirt2. K9 acetylation of stathmin1 inhibited the combining of stathmin1 to E3 ubiquitin ligase RLIM, thereby inhibiting its ubiquitination degradation. Moreover, K9 acetylation also promoted the activity of stahtmin1 interacting and destabilizing microtubule through the inhibition of stathmin1 phosphorylation. K9 acetylated stathmin1 significantly promoted gallbladder cancer cell migration and invasion viability in vitro and lung metastasis in vivo, and indicated poor prognosis of nude mice. IHC assay suggested the positive correlation of high levels of K9 acetylation and stathmin1 expression in gallbladder cancer. Our study revealed that K9 acetylation up-regulated stathmin1 protein stability and microtubule-destabilizing activity to promoted gallbladder cancer metastasis, which provides a potential target for gallbladder cancer therapy.

Non-lysine ubiquitylation: Doing things differently

“…Perhaps one of the most obvious benefits of expanding ubiquitylation to include residues beyond lysine is that it affords the opportunity for crosstalk with additional post-translational modifications (PTMs), at the same time avoiding competition with lysine-targeted PTMs such as acetylation, which has been reported to prevent substrate ubiquitylation and suppress isopeptide-linked ubiquitin chain formation ( Gronroos et al, 2002 ; Ito et al, 2002 ; Vervoorts et al, 2003 ; Bernassola et al, 2004 ; Jin et al, 2004 ; Simonsson et al, 2005 ; Le Cam et al, 2006 ; Min et al, 2010 ; Ohtake et al, 2015 ; Fan et al, 2022 ). The complex interplay between ubiquitylation and protein phosphorylation is well established and has been extensively reviewed elsewhere (see, for example, Hunter 2007 ; Chen and Chen 2013 ; Nguyen et al, 2013 ; Cohen 2014 ; Schwertman et al, 2016 ; Filipcik et al, 2017 ; Song and Luo 2019 ; Zhang and Zeng 2020 ; Dang et al, 2021 ; Lacoursiere et al, 2022 ).…”