S119N Mutation of the E3 Ubiquitin Ligase SPOP Suppresses SLC7A1 Degradation to Regulate Hepatoblastoma Progression

Abstract

A previous study on hepatoblastoma revealed novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex, including the tumor suppressor speckle-type BTB/POZ (SPOP). Moreover, the SPOP gene affected cell growth, and its S119N mutation was identified as a loss-of-function mutation in hepatoblastoma. This study aimed to explore more functions and the potential mechanism of SPOP and its S119N mutation. The in vitro effects of SPOP on cell proliferation, invasion, apoptosis, and in vivo tumor growth were investigated by western blot analysis, Cell Counting Kit-8, colony formation assay, flow cytometry, and xenograft animal experiments. The substrate of SPOP was discovered by a protein quantification assay and quantitative ubiquitination modification assay. The present study further proved that SPOP functioned as an anti-oncogene through the phosphatidylinositol 3-kinase/Akt signaling pathway to affect various malignant biological behaviors of hepatoblastoma both in vitro and in vivo . Furthermore, experimental results also suggested that solute carrier family 7 member 1 (SLC7A1) might be a substrate of SPOP and influence cell phenotype by regulating arginine metabolism. In conclusion, these findings demonstrated the function of SPOP and revealed a potential substrate related to hepatoblastoma tumorigenesis, which might thus provide a novel therapeutic target for hepatoblastoma.

A comprehensive analysis of the diagnostic and prognostic value associated with the SLC7A family members in breast cancer

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Comprehensive Analysis of Inflammation Response Related Genes and Immune Infiltrates in Osteosarcoma

“…The combination of CD62L targeted drugs and immunotherapy is viable in enhancing the antitumor e cacy [39]. SLC7A1 is a transporter that responsible for the uptake of cationic amino acids uptake function, and such function is essential for cellular growth [40]. At present, studies on these IRG genes in osteosarcoma is less reported.…”

SPOP in Cancer: Phenomena, Mechanisms and Its Role in Therapeutic Implications

“…The SPOP substrates in these cancers include: ERα [ 35 , 95 ], and BRD 2/3/4 in endometrial cancer [ 19 ], ERα [ 96 ], PR [ 37 ], SRC3 [ 25 ], c-MYC [ 36 ], BRMS1 [ 38 ], ASCT2 in breast cancer [ 97 ], Gli2 in gastric cancer [ 98 ], Gli2 [ 99 ], HDAC6 in colorectal cancer (CRC) [ 100 ], and MyD88 and CHAF1A in diffuse large B-cell lymphoma (DLBLC) [ 101 , 102 , 103 , 104 ]. Fas-associated death domain protein (FADD) [ 105 ], SIRT2 in lung cancer (LC) [ 106 ], SENP7 in hepatocellular carcinoma (HCC) [ 107 ], DHX9 in choriocarcinoma [ 108 ], FLI1 in Ewing sarcoma [ 109 ], and SLC7A1 [ 110 ], DRAK1 and PIPKIIβ in cervical cancer (CC) [ 111 , 112 ]. Figure 3 b summarizes the different SPOP substrates and their functions in cellular processes reported in different cancers.…”