RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing RNF31

Abstract

RNF31 (HOIP), RBCK1 (HOIL-1L), and SHARPIN are subunits of the linear ubiquitin chain assembly complex. Their function and specific molecular mechanisms in hepatocellular carcinoma (HCC) have not been reported previously. Here, we investigated the role of RNF31 and RBCK1 in HCC. We showed that RNF31 and RBCK1 were overexpressed in HCC and that upregulation of RNF31 and RBCK1 indicated poor clinical outcomes in patients with HCC. RNF31 overexpression was significantly associated with more satellite foci and vascular invasion in patients with HCC. Additionally, RBCK1 expression correlated positively with RNF31 expression in HCC tissues. Functionally, RBCK1 and RNF31 promote the metastasis and growth of HCC cells. Moreover, the RNF31 inhibitor gliotoxin inhibited the malignant behavior of HCC cells. Mechanistically, RBCK1 interacted with RNF31 and repressed its ubiquitination and proteasomal degradation. In summary, the present study revealed an oncogenic role and regulatory relationship between RBCK1 and RNF31 in facilitating proliferation and metastasis in HCC, suggesting that they are potential prognostic markers and therapeutic targets for HCC.

RNF31 promotes proliferation and invasion of hepatocellular carcinoma via nuclear factor kappaB activation

“…Because RNF31 and RBCK1 are both essential components of the LUBAC, we suspected that the stabilization of RNF31 by RBCK1 could increase LUBAC formation and subsequently trigger enhanced NF-κB activation via linear ubiquitination. Consistent with this, Chen et al showed that gliotoxin, an inhibitor of LUBAC activity, has inhibitory effects on HCC cell lines 25 . However, they did not clarify whether the inhibitory effect of gliotoxin was due to LUBAC or NF-κB activity, as gliotoxin itself has cytotoxicity 23 .…”

“…However, in our cohort, RNF31 expression was not correlated with viral hepatitis or liver cirrhosis. Chen et al also reported that there was no correlation between RNF31 expression and HBV or cirrhosis 25 .…”

“…As a mechanism of RNF31 in HCC, Chen et al suggested that RBCK1 could promote HCC metastasis and growth by stabilizing RNF31 25 . Because RNF31 and RBCK1 are both essential components of the LUBAC, we suspected that the stabilization of RNF31 by RBCK1 could increase LUBAC formation and subsequently trigger enhanced NF-κB activation via linear ubiquitination.…”

RBCK1 promotes the stabilization of HBx by linear ubiquitination to drive the progression of HBV-associated hepatocellular carcinoma

“…In the previous studies, it had been reported that the expression of RBCK1 and Sharpin was upregulated in tumor tissues [29,30], and exerted oncogenic functions by stabilizing the expression RNF31 and promoting the transactivation of Versican expression; however, it was independent of their M1-Ubi activity. Thus, a more comprehensive study is needed on the potential functions of M1-Ubi and LUBAC components in HCC, especially in HBV-associated HCC.…”

“…Recently, quite a few E3 ubiquitin ligases have exhibited abnormal expression in tumors, making them valuable diagnostic markers and drug targets [32]. Previous studies have revealed that publicly-available databases and in vitro analysis have determined that mRNA expression of RBCK1 in HCC cells and tissues was significantly higher than those of normal counterparts [30,33]. For factors upregulating the expression of RBCK1, Queisser MA et al .…”