TRIM71 suppresses tumorigenesis via modulation of Lin28B-let-7-HMGA2 signaling

Abstract

TRIM71 (tripartite motif-containing 71) belongs to the TRIM-NHL protein family, which plays a conserved role in regulating early development and differentiation. However, the molecular functions of TRIM71 have remained largely unknown. Here, we explored the role of TRIM71 together with modulation of Lin28B-let-7-HMGA2 (high-mobility group AT-hook 2) signaling in tumorigenesis. TRIM71 overexpression opposed Lin28B-induced transformation in primary cells and inhibited tumor formation in a mouse model. Specific knockdown of TRIM71 expression increased cancer cell proliferation and invasion. Conversely, overexpression of wild-type TRIM71 in non-small cell lung carcinoma (NSCLC) cells in which Lin28B-let-7-HMGA2 signaling was conserved decreased both cancer cell phenotypes. More importantly, overexpression of an ubiquitin transfer activity-deficient TRIM71 mutant in NSCLC cells had no effect on proliferation or invasion, regardless of the conservation status of Lin28B-let-7-HMGA2 signaling. The tumorigenic inhibitory action of TRIM71 was antagonized by overexpression of the TRIM71 downstream targets, Lin28B and HMGA2. Furthermore, a bioinformatics analysis revealed that TRIM71 expression was downregulated in various types of cancer tissue from patients. Taken together, these data indicate that TRIM71 acts through post-transcriptional repression of Lin28B and subsequent modulation of let-7-HMGA2 signaling during tumorigenesis to potentially function as a tumor suppressor.

E3 ubiquitin ligase tripartite motif-containing 71 promotes the proliferation of non-small cell lung cancer through the inhibitor of kappaB-α/nuclear factor kappaB pathway

“…The RING motif of TRIM71 is essential for target protein ubiquitin-dependent degradation or stabilization. TRIM71 acts as a specific E3 ubiquitin ligase, downregulates the expression of AGO proteins [ 14 , 15 ] and the RNA-induced silencing complex components, and promotes the expression of let-7 downstream target proteins [ 16 – 18 ]. Moreover, TRIM71 has been shown to stabilize Shc SH2-binding protein 1 (SHCBP1), a component of fibroblast growth factor (FGF) signaling, via ubiquitination and to enhance FGF signaling in neuronal progenitor cells [ 19 ].…”

PCAF-mediated acetylation of Lin28B increases let-7 biogenesis in lung adenocarcinoma H1299 cells

“…Although we have previously reported that the protein level of Lin28A had decreases in PCAF-transfected cells [ 26 ], Lin28B was not substantially changed at the protein level (data not shown). Both Lin28A and Lin28B interact with PCAF via their CSD, and let-7 binds to the 3’UTR of both Lin28 paralogs, thereby repressing Lin28 translation in a negative feedback loop; however, TRIM71, a specific E3 ubiquitin ligase, negatively regulates Lin28B (but not Lin28A) protein levels by ubiquitinating its C-terminal unique region, which is absent in the Lin28A paralog [ 24 , 25 ]. It might be interesting to study whether the acetylation of Lin28B by PCAF affects the poly-ubiquitination of Lin28B at the C-terminal region and may alter its stability.…”

“…Protein acetylation is known to participate in regulating multiple cellular processes in normal and cancer cells [ 21 – 23 ]. As a bona fide cancer-related protein, Lin28B is subject to polyubiquitination that leads to the enhancement of let-7 biogenesis [ 24 , 25 ]. However, whether the acetylation of Lin28B affects the let-7 biogenesis involved in tumorigenesis is not yet fully understood.…”

Cancer Simulation from Stage Minus One by Quantum microRNA Language: Lung, Colorectal and Pancreatic Cancers

“…Although Lin28B upregulation by downregulation of let-7-5p family was simulated in Figure 5B, Lin28B could further repress let-7-5p family expression via human ubiquitin ligase TRIM71 [123]. On the other hand, super-downregulation of let-7-5p would increase TRIM71 ( Figure 5C) and TRIM71 overexpression opposed Lin28B-inducing transformation [124]. Since downregulation of miR-203a-3p and let-7-5p family would increase TRIM71 ( Figure 5C), Figure 5B).…”