A MicroRNA/Ubiquitin Ligase Feedback Loop Regulates Slug-Mediated Invasion in Breast Cancer

Abstract

The transformation of a normal cell to cancer requires the derail of multiple pathways. Normal signaling in a cell is regulated at multiple stages by the presence of feedback loops, calibration of levels of proteins by their regulated turnover, and posttranscriptional regulation, to name a few. The tumor suppressor protein FBXO31 is a component of the SCF E3 ubiquitin ligase and is required to arrest cells at G1 following genotoxic stresses. Due to its growth-suppression activity, it is underexpressed in many cancers. However, the molecular mechanism underlying the translational regulation of FBXO31 remains unclear. Here we show that the oncogenic microRNAs miR-93 and miR-106a repress FBXO31, resulting in the upregulation of Slug, which is involved in epithelial-mesenchymal transition and cell invasion. FBXO31 targets and ubiquitylates Slug for proteasomal degradation. However, this mechanism is repressed in breast tumors where miR-93 and miR-106a are overexpressed. Our study further unravels an interesting mechanism whereby Slug drives the expression of miR-93 and miR-106a, thus establishing a positive feedback loop to maintain an invasive phenotype. Together, these results establish the presence of interplay between microRNAs and the ubiquitination machinery, which together regulate cancer cell invasion.

The role of F‑box only protein 31 in cancer (Review)

“…Furthermore, it was suggested that FBXO31 targets mouse double minute 2 homolog (MDM2) during ubiquitination and degradation, leading to elevated p53 levels, cell cycle arrest and growth inhibition, supporting the tumor suppressive role of FBXO31 in breast cancer ( 27 ). In addition, Manne et al ( 39 ) demonstrated that FBXO31 targets the Snail family transcriptional repressor protein 2 (Slug), which is involved in the epithelial-mesenchymal transition, cell invasion, ubiquitination and degradation, and therefore represses the growth of breast cancer cells. Studies have determined that micro (mi)RNAs are dysregulated at all stages of breast cancer and serve important roles in tumorigenesis, invasion and metastasis ( 40 , 41 ).…”

“…Subsequently, the tumor suppressive effect of miR-210 downregulation may be reversed by further depletion of FBXO31. A study by Manne et al ( 39 ) indicated that the oncogenic miRNAs miR93 and miR106a repressed FBXO31 expression, thus impairing the degradation of Slug via FBXO31.…”

Systematic analysis of the expression and prognosis relevance of FBXO family reveals the significance of FBXO1 in human breast cancer

“…FBXO31 targets and ubiquitylates Slug for proteasomal degradation. Due to its growth-suppression activity, it is underexpressed in many kinds of cancers [53]. High-regulation of FBXO31 inhibits the proliferation and colony formation of breast tumor cells by mediating ubiquitination and degradation of spci c substrates, and then inhibits cancer progression [23].…”

Poly r(C) binding protein 1‐mediated regulation of microRNA expression underlies post‐sevoflurane amelioration of acute lung injury in rats

“…It was recently shown that in the context of breast cancer miR‐93 and miR‐106a, which repress the E3 ligase FBXO31 that targets the pro‐metastatic Slug, are downregulated. This mechanism is repressed in metastatic breast cancer where high miR‐93 and miR‐106a levels ensures that Slug is expressed, which was then shown to further potentiate miR‐93 and miR‐106a levels by establishing a positive feedback loop (Manne et al, ). Hence, another alternative mechanism can be that increased PCBP1 expression during LPS‐induced ALI directly increases pro‐inflammatory cytokines by increasing their transcription in a similar feed‐forward mechanism.…”