NIK-mediated reactivation of SIX2 enhanced the CSC-like traits of hepatocellular carcinoma cells through suppressing ubiquitin-proteasome system.

Abstract

The critical roles of NF-κB Inducing Kinase (NIK) in tumor progression have been elucidated in various tumors; however, its effects on hepatocellular carcinoma (HCC) progression are still confusing. Here, we found that NIK level was upregulated in HCC tissues compared to that of normal tissues, and positively correlated with the levels of cancer stem cell (CSC) markers. Then we established HCC cells with NIK-stable knockdown and found that NIK knockdown suppressed the CSC-like traits of HCC cells through in vivo and in vitro experiments. Mechanistically, we revealed that SIX2 protein level, but not its mRNA level, was significantly reduced in HCC cells with NIK knockdown, which was rescued by MG132 treatment. Furthermore, NIK knockdown promoted the ubiquitination level of SIX2 and decreased its protein stability. Moreover, Six2 overexpression partially reversed the inhibition of NIK knockdown on the CSC-like traits of HCC cells. This study identified a novel NIK/SIX2 axis conferring HCC stemness.