TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA

Abstract

A hypoxic tumor microenvironment (TME) promotes cancer progression, yet its value as a therapeutic target remains underexploited. Tripartite motif-containing 72 (TRIM72) may protect cells against various stresses including hypoxia. Recently, low TRIM72 expression has been implicated in cancer progression. However, the biological role and molecular mechanism of TRIM72 in breast cancer (BC) remain unclear. Herein, we analyzed the TRIM72 expression in BC tissue and cell lines by western blot (WB) and quantitative reverse transcription-PCR. We established the overexpression of TRIM72 using plasmids and lentiviral-mediated upregulation, as well as downregulation of protein phosphatase 3 catalytic subunit alpha (PPP3CA) by siRNA. The tumor-suppressive roles of TRIM72 were assessed on BT549 and MDA-MB-231 cells by MTS, Transwell, and flow cytometry assays in vitro and in xenografted tumors in vivo . The molecular mechanism of TRIM72 was investigated by luciferase reporter and co-immunoprecipitation (Co-IP) assay. Lactate production was measured by ELISA under hypoxic environments induced by CoCl 2 . Moreover, the expression of PI3K/Akt/mTOR pathway-associated proteins was detected by WB in BC cells. Results showed that TRIM72 was downregulated in BC. Overexpression of TRIM72 inhibited tumor proliferation and invasion in vitro and in a xenograft tumor model. Mechanistically, PPP3CA altered the inhibitory effects of TRIM72 on hypoxia-induced lactate production and monocarboxylate transporter 4-promoter activity, as well as the effect of the PI3K/Akt/mTOR signaling pathway. Our study suggests that TRIM72 modulates the TME and plays tumor-suppressive roles in BC progression. Therefore, TRIM72 may serve as a potential therapeutic target in BC.

Identification of somatic mutation-driven enhancers and their clinical utility in breast cancer

“… 21 Overexpression of TRIM72 is reported to inhibit tumor proliferation and invasion in vitro and in a xenograft tumor model in breast cancer progression. 22 The “DEL” mutation in the “chr3:57896344-57896845” significantly increased the activity of the enhancer (log2FC = 2.31) in LumB subtype, which in turn was associated with the downregulation of potential target genes, such as lncRNA FLNB-AS1, FLNB, and SLMAP. The lncRNA FLNB-AS1 was significantly downregulated (log2FC = −2.34) in breast cancer samples with the mutation-driven enhancer, and literature has confirmed that FLNB-AS1 is positively correlated with the survival probability of patients with breast cancer.…”

TRIM72 Alleviates Muscle Inflammation in mdx Mice via Promoting Mitophagy-Mediated NLRP3 Inflammasome Inactivation

“…The activation of ULK1 complex is essential for phagophore and regulated by PI3K-AKT-mTOR pathway [ 39 ]. Recent studies have shown that TRIM72 could suppress the PI3K-AKT-mTOR pathway induced by hypoxia [ 58 ]. Here, we also found that AAV-TRIM72 decreased the p-PI3K and p-AKT expression (Figures 6(a) – 6(c) ).…”

MG53/TRIM72: multi-organ repair protein and beyond

“…An analysis of ubiquitinrelated genes in the cancer genome atlas queue revealed an association between MG53 and the prognosis of renal clear cell carcinoma (Wu et al, 2021). MG53 can also impede breast cancer progression by suppressing the activation of the PI3K/Akt/mTOR pathway (Wang et al, 2022). Further investigation is warranted to explore the potential anti-tumor effects of MG53 in various malignancies.…”