Down-regulation of salt-inducible kinase 1 (SIK1) is mediated by RNF2 in hepatocarcinogenesis

Abstract

Our previous study reported that down-regulation of SIK1 accelerates the growth and invasion of hepatocellular carcinoma (HCC). However, the underlying mechanism leading to SIK1 down-regulation in HCC largely remains to be determined. Herein, we demonstrated that RNF2 expression is negatively correlated with SIK1 levels in HCC tissues. Kaplan-Meier analysis of tumor samples revealed that high RNF2 expression with concurrent low SIK1 expression is associated with poor overall survival. The down-regulation of RNF2 expression in HCC cells significantly reduces tumor cell growth and metastasis, while the simultaneous down-regulation of both RNF2 and SIK1 restores tumor cell growth in vitro and in tumor xenograft models. Mechanistically, we identified RNF2 as an E3 ligase that targets SIK1 for degradation. We further demonstrated that direct physical interaction between RNF2 and SIK1 triggers SIK1 down-regulation in HCC cells. These data suggest that RNF2 is an important upstream negative regulator of SIK1 and that restoration of SIK1 levels induced by loss of RNF2 inhibited HCC cell growth and promoted apoptosis, which may represent a promising therapeutic strategy for HCC treatment.

The protein kinase SIK downregulates the polarity protein Par3

“…Since we have shown that SIK also binds to TGFβRI and together with Smurf2 promotes degradation of TGFβRI [ 23 ], we consider favorably the possibility of involvement of Smurf E3 ligases in the degradation mechanism of Par3, opening up an exciting scenario of coordinate TJ and polarity regulation by ubiquitination. On the other hand, RNF2 that ubiquitinates and degrades SIK [ 54 ], may also be involved in Par3 degradation, assuming that an unknown mechanism enforces cytoplasmic residence of RNF2; the latter is compatible with our observations that support coordinate degradation of SIK and Par3 (Figure 3 , 4 ).…”

“…Twist1 would also transcriptionally repress the SIK gene, explaining the low SIK expression in aggressive HCCs [ 53 ]. Furthermore, the low levels of SIK protein in aggressive HCC are maintained by the nuclear ubiquitin ligase RNF2, a subunit of the Polycomb co-repressor complex 1 [ 54 ]. Additional studies in lung and kidney epithelial cells support the nuclear actions of SIK.…”

Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response

“…Another example of a relatively under-studied transcript up-regulated by YM-155, is salt inducible kinase 1 (SIK1) which is evident at both time points [+5.04, p<0.001, 8 h/ +8.06, p<0.001, 20 h]. Like FOSB, SIK1 has been reported as a tumor suppressor capable of halting tumor growth, metastasis and rendering greater overall survival rates (44,45). Likewise, numerous studies are now reporting that a reduction of SIK1 is associated with drug/adiation resistance, aggressive tumor pathologies and greater likelihood of epithelial-mesenchymal transition (46)(47)(48).…”

Enhanced intratumoral expression of RNF2 is a favorable prognostic factor for patients with cutaneous melanoma?

“…Interestingly several studies published up to now described worsening of prognoses with increased RNF2 expression in cancers of pancreas [ 14 ], esophagus [ 15 ], liver [ 16 ], urinary bladder [ 17 ] and ovary [ 18 ]. It is possible that spectrum of genes actively modulated by RNF2 changes in different cell types [ 10 , 19 , 20 ].…”