TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours

Abstract

BackgroundTRIM8 plays a key role in controlling the p53 molecular switch that sustains the transcriptional activation of cell cycle arrest genes and response to chemotherapeutic drugs. The mechanisms that regulate TRIM8, especially in cancers like clear cell Renal Cell Carcinoma (ccRCC) and colorectal cancer (CRC) where it is low expressed, are still unknown. However, recent studies suggest the potential involvement of some microRNAs belonging to miR-17-92 and its paralogous clusters, which could include TRIM8 in a more complex pathway.MethodsWe used RCC and CRC cell models for in-vitro experiments, and ccRCC patients and xenograft transplanted mice for in vivo assessments. To measure microRNAs levels we performed RT-qPCR, while steady-states of TRIM8, p53, p21 and N-MYC were quantified at protein level by Western Blotting as well as at transcript level by RT-qPCR. Luciferase reporter assays were performed to assess the interaction between TRIM8 and specific miRNAs, and the potential effects of this interaction on TRIM8 expression. Moreover, we treated our cell models with conventional chemotherapeutic drugs or tyrosine kinase inhibitors, and measured their response in terms of cell proliferation by MTT and colony suppression assays.ResultsWe showed that TRIM8 is a target of miR-17-5p and miR-106b-5p, whose expression is promoted by N-MYC, and that alterations of their levels affect cell proliferation, acting on the TRIM8 transcripts stability, as confirmed in ccRCC patients and cell lines. In addition, reducing the levels of miR-17-5p/miR-106b-5p, we increased the chemo-sensitivity of RCC/CRC-derived cells to anti-tumour drugs used in the clinic. Intriguingly, this occurs, on one hand, by recovering the p53 tumour suppressor activity in a TRIM8-dependent fashion and, on the other hand, by promoting the transcription of miR-34a that turns off the oncogenic action of N-MYC. This ultimately leads to cell proliferation reduction or block, observed also in colon cancer xenografts overexpressing TRIM8.ConclusionsIn this paper we provided evidence that TRIM8 and its regulators miR-17-5p and miR-106b-5 participate to a feedback loop controlling cell proliferation through the reciprocal modulation of p53, miR-34a and N-MYC. Our experiments pointed out that this axis is pivotal in defining drug responsiveness of cancers such ccRCC and CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0634-7) contains supplementary material, which is available to authorized users.

<p>miR-106b promotes proliferation and invasion by targeting Capicua through MAPK signaling in renal carcinoma cancer</p>

“…47 Mastropasqua et al, showed N-Myc dependent overexpressed miR-106b promoted chemoresistance via regulating of tripartite motif containing 8 (TRIM8) in colorectal cancer. 48 On the contrary, demonstrated miR-106b was downregulated in cisplatin-resistance lung cancer cell lines when compared with sensitive parental cells, 13 also forced overexpression of miR-106b was associated with increased sensitivity of cancer cells to cisplatin in testicular embryonal carcinoma. 49 Collectively, the studies discussed above indicated that miR-106b might have different effects on cellular processes including cellular progression and chemoresistance in various types of human cancer.…”

Inhibition of USP14 and UCH37 deubiquitinating activity by b-AP15 as a potential therapy for tumors with p53 deficiency

“…Tumor-suppressor protein p53 is important for cell function and genome integrity. 1 The decrease of p53 protein is a common feature of human malignant tumors, which leads to the deficiency of cell cycle detection point control and apoptosis induction. An enormous amount of research effort goes into small molecules that regulate p53, including wild-type repair of mutant p53 gene and interruption of the binding between p53 and an E3-ubiquitin ligase Mdm2 to prevent ubiquitination degradation of p53 and rescue the protein level of p53.…”

Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways

“…In cancer research, Trim8 is down regulated in glioma affects cell proliferation and is associated with patient survival [24]. Trim8 also regulates stemness in glioblastoma through PIAS3-STAT3 [25] and inhibits tumour growth by restoring p53 tumour suppressor function through blunting of N-MYC activity in chemoresistant tumours [26]. In innate immunity under human non-alcoholic fatty liver disease and non-alcoholic steatohepatitis conditions, the function of Trim8 involves targeting of TAK1 to promote insulin resistance and steatohepatitis.…”