Targeting TRIM54/Axin1/β-Catenin Axis Prohibits Proliferation and Metastasis in Hepatocellular Carcinoma

Abstract

Accumulating evidence demonstrates that dysregulation of ubiquitin-mediated degradation of oncogene or suppressors plays an important role in several diseases. However, the function and molecular mechanisms of ubiquitin ligases underlying hepatocellular carcinoma (HCC) remain elusive. In the current study, we show that overexpression of TRIM54 was associated with HCC progression. TRIM54 overexpression facilitates proliferation and lung metastasis; however, inhibition of TRIM54 significantly suppressed HCC progression both in vitro and in vivo. Mechanically, we demonstrated that TRIM54 directly interacts with Axis inhibition proteins 1 (Axin1) and induces E3 ligase-dependent proteasomal turnover of Axin1 and substantially induces sustained activation of wnt/β-catenin in HCC cell lines. Furthermore, we showed that inhibition of the wnt/β-catenin signaling pathway via small molecule inhibitors significantly suppressed TRIM54-induced proliferation. Our data suggest that TRIM54 might function as an oncogenic gene and targeting the TRIM54/Axin1/β-catenin axis signaling may be a promising prognostic factor and a valuable therapeutic target for HCC.

Ubiquitin-proteasome system-based signature to predict the prognosis and drug sensitivity of hepatocellular carcinoma

“…Furthermore, SOCS2 enhances the radiotherapy sensitivity of patients with HCC through mediated SLC7A11 ubiquitination ( Chen et al, 2022 ). Furthermore, TRIM54 was identified as an oncogene in HCC ( Zhu et al, 2021 ). Köster et al have demonstrated that a high level of PSMD9 is strongly associated with clinical relapse after radiotherapy in patients with cervical cancer ( Köster et al, 2020 ).…”

TRIM37 promotes gallbladder cancer proliferation by activating the Wnt/β-catenin pathway via ubiquitination of Axin1

“…In GBC cells, TRIM37 has been found to interact with Wnt/β‑catenin signaling pathway, although the mechanisms behind this remain unknown [ 11 , 12 , [18] , [19] , [20] , [21] ]. It has been shown in previous studies that the E3 ubiquitin ligases, such as RNF146, TRIM11, TRIM32, TRIM54, TRIM65 and UBE3C promote various cancers by triggering Wnt/β-catenin signaling via degradation of Axin1 [22] , [23] , [24] , [25] , [26] , [27] . Axin1 and GSK-3β are two key regulators of the Wnt/β-Catenin pathway.…”

RNF149 confers cisplatin resistance in esophageal squamous cell carcinoma via destabilization of PHLPP2 and activating PI3K/AKT signalling

“…Immunoprecipitation was performed according to our published studies [20]. Lysates from 3 × 10 6 cells transfected with the indicated constructs were incubated with myc-, or Flag-conjugated agarose beads (Sigma-Aldrich, Germany) overnight at 4°C.…”

“…Western blotting was performed according to our published studies [20]. The primary antibodies were:antiag (Sigma-Aldrich, F3165), anti-RNF149 (HPA011424, Sigma-Aldrich), anti-myc (ab32, Abcam), anti-HA (Abcam, ab9110), and anti-PHLPP2 (ab227673, Abcam).…”