Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

Abstract

The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitinindependent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.

SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation

“…Thus, there are potentially several mechanisms that could mediate positive feedback stabilization of PTEN-PI3K-AKT signaling through SOX4 activity (Figure 5). Moreover, our finding that inhibition of the proteasome partially restores SOX4 expression are consistent with a model in which AKT phosphorylation of the transactivation domain of SOX4, which also controls proteasomal degradation of SOX4 (32), enhances protein stability by inhibiting ubiquitin-mediated proteolysis. Our analysis of Achilles and CCLE datasets across 215 cell lines from 20 tissue types supports the hypothesis that SOX4 interactions with AKT1 are important in many types of cancer, and also suggests that drug combinations that target both SOX4 and PI3K-AKT might have synergistic effects.…”

Increased production of intestinal immunoglobulins in Syntenin-1-deficient mice

“…IL-5R-specific ␣ subunit (IL-5R␣) and a common ␤ subunit for the GM-CSF receptor family (Mita et al, 1989). Syntenin-1 was reported to associate with the cytoplasmic tail of IL-5R␣ through the PDZ (PSD-95/Discs large/zO-1) domain and to interact directly with the transcription factor Sox4 (Beekman et al, 2009(Beekman et al, , 2012Geijsen et al, 2001). Interestingly, Sox4 promotes B cell development, as determined by analysis of Sox4 KO mice (Schilham et al, 1996;Sun et al, 2013).…”

Knockout of MDA-9/Syntenin (SDCBP) expression in the microenvironment dampens tumor-supporting inflammation and inhibits melanoma metastasis

“…We provided definitive evidence that mda-9/syntenin is a pro-metastatic gene when expressed in immortal normal human cells and in human cancer cells of diverse origin with an ability to induce invasion and experimental metastasis [7–11]. The diverse roles of mda-9/syntenin (SDCBP) in exosome biogenesis [12–16], intracellular trafficking [17, 18], neuronal differentiation [19–21], immune cell migration [22–25] and anti-viral activity [26, 27] are also current areas of intense investigation in multiple laboratories. In total, these studies validate the functional importance of MDA-9/Syntenin in maintaining both normal cellular physiology and promoting cancer progression.…”