TENT5A mediates the cancer-inhibiting effects of EGR1 by suppressing the protein stability of RPL35 in hepatocellular carcinoma

Terminal nucleotidyltransferase 5A (TENT5A), recently predicted as a non-canonical poly(A) polymerase, is critically involved in several human disorders including retinitis pigmentosa, cancer and obesity. However, the exact biological role of TENT5A in hepatocellular carcinoma (HCC) has not been elucidated.

The transcription level of TENT5A and clinical correlation were analyzed using the LIRI-JP cohort, the TCGA-LIHC cohort, and clinical tissue samples of HCC patients in our laboratory. Proliferation, migration, and invasion were detected with stably TENT5A overexpressing and knockdown HCC cells in vitro and in vivo. Chromatin immunoprecipitation and dual-luciferase reporter assay were performed to verify the binding of the target protein to DNA. Co-immunoprecipitation and GST pull-down assay combined with mass spectrometry (MS) were used to identify protein interactions.

Our study presented here shows that TENT5A is downregulated in HCC tissues, suggesting a shorter overall survival for patients. Gain- and loss-of-function experiments reveal that TENT5A suppresses the proliferation and metastasis, and the residue Gly¹²² is of great importance to the role of TENT5A in HCC. More importantly, EGR1 (Early growth response 1) directly binds to the TENT5A promoter and promotes TENT5A expression. By interacting with RPL35, TENT5A is involved in ribosome biogenesis and exerts a negative regulatory effect on the mTOR pathway.

Our findings illustrate the role of the oncosuppressive function of TENT5A in HCC and suggest that the EGR1/TENT5A/RPL35 regulatory axis may be a promising target for therapeutic strategies in HCC.