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Potential contribution of SET and c‐MYC deregulation to promote extracellular matrix remodelling in hepatocellular carcinoma

The recent publication by Ward and Spiers (2017) provides novel interesting findings about the relevance of protein phosphatase 2A (PP2A) as a regulator of extracellular matrix remodelling in human hepatocellular carcinoma (HCC). The authors showed that both okadaic acid and cancerous inhibitor of PP2A (CIP2A)-mediated PP2A inhibition caused increased MMP-9 levels. Of note, MMP-9 expression was enhanced at the transcriptional level through the activation of the PP2A-regulated transcription factor activator protein 1 (AP-1) and binding to specific AP-1 sites in theMMP-9 promoter. Interestingly, the authors demonstrated that the knockdownof PPP2R1Ahadno effects on MMP-9 expression. As the presence of the scaffolding PP2A subunit is critical for the formation of a functional hetrotrimeric complex, it would be very interesting to explore whether the PPP2R1B subunit controls the role of PP2A as an AP-1-mediated MMP-9 regulator. In their discussion, the authors claimed that the endogenous PP2A inhibitor SET has been reported to reduce MMP9 levels in head and neck squamous cell carcinoma (Sobral et al., 2014). However, this observation has not been further confirmed. In fact, several other works have highlighted that SET enhances MMP-9 expression in breast (Li et al., 2014) and more recently in non-small cell lung cancer (Liu et al., 2015). Moreover, one would expect a positive role of SET on MMP-9 activity since SET has been reported to increase AP-1 activity (Al-Murrani et al., 1999) based on its ability to inhibit PP2A, a phosphatase which directly dephosporylates and inactivates AP-1. Therefore, the contribution of SET to the regulation of MMP-9 in HCC should be clarified in forthcoming studies, especially as SET has frequently been demonstrated to be overexpressed in this disease. Another relevant issue to further determine the role of PP2A in the transcriptional control of MMP-9 would be that the transcription factor MYC proto-oncogene (c-MYC) has been reported to specifically bind to the MMP-9 promoter, thereby driving its transcription (Magid et al., 2003). As CIP2A is a key post-translational regulator of c-MYC, through its ability to impair its PP2A-induced dephosphorylation and proteosomal degradation, and as SET has also been reported to positively control c-MYC, the specific contribution of this transcription factor should also be investigated in addition to AP-1. Altogether, the work by Ward and Spiers suggests that MMP-9 deregulation is a relevant event in HCC, which contributes to tumour invasion. Importantly, this alteration could be targeted by the pharmacological activation of PP2A using drugs such as FTY720, which impairs the function of both SET and CIP2A and has shown promising antitumour effects in this disease.