Ring finger protein 152-dependent degradation of TSPAN12 suppresses hepatocellular carcinoma progression

Abstract

Background Hepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear. Methods Transcriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152. Results We found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression. Conclusion Collectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.

RNF150 suppresses papillary thyroid carcinoma with ASK1 ubiquitination presenting a direct target via inactivating p38 signaling axis

“…Moreover, RNF183 could confer resistance to trametinib in colorectal cancer and promote the metastasis (Geng et al, 2017). In contrast, RNF152 could suppress the proliferation of hepatocellular carcinoma and was a prognostic biomarker for colorectal cancer (Cui et al, 2018; Wan et al, 2021). Ding et al reported that RNF150 was associated with the risk of COPD patients (Ding, Niu, 2015a).…”

SOX2‐positive retinal stem cells are identified in adult human pars plicata by single‐cell transcriptomic analyses

“… 59 Additionally, TSPAN12 has been reported to be a proliferation‐promoting regulatory factor in a variety of neoplastic diseases, including small‐cell lung carcinoma, non‐small cell lung carcinoma, ovarian cancer, and hepatocellular carcinoma. 41 , 60 , 61 , 62 Furthermore, TSPAN12 functions as an important regulator of retinal vascular development by promoting Norrin‐induced FZD4/beta‐catenin signaling. 63 Previous studies combined with our results suggest that AQP1 and TSPAN12 are expected to be potential proliferation markers for SOX2‐positive RSCs.…”

“…Moreover, there exists a correlation between the aquaporin expression profile and neural differentiation 59 . Additionally, TSPAN12 has been reported to be a proliferation‐promoting regulatory factor in a variety of neoplastic diseases, including small‐cell lung carcinoma, non‐small cell lung carcinoma, ovarian cancer, and hepatocellular carcinoma 41,60–62 . Furthermore, TSPAN12 functions as an important regulator of retinal vascular development by promoting Norrin‐induced FZD4/beta‐catenin signaling 63 .…”

Membrane-Associated Ubiquitin Ligase RING Finger Protein 152 Orchestrates Melanogenesis via Tyrosinase Ubiquitination

“…RNF152 acts as a positive regulator of TLR/IL-1Rmediated signaling by promoting oligomerization of MyD88 [14]. Additionally, RNF152 targets TSPAN12 for ubiquitination and subsequent proteasomal degradation, resulting in the suppression of hepatocellular carcinoma cell proliferation [15]. RNF152, along with RNF182, RNF183, and RNF186, constitutes the RNF183 family, consisting of closely related genes encoding a RING-finger domain (C3HC4) at their N-terminus and one or two predicted transmembrane domains at their C-terminus with high homology [16].…”