MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15–20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.

Integrated Analysis of RNA Binding Protein-Related lncRNA Prognostic Signature for Breast Cancer Patients

“…Thus, the exploration of potential prognostic biomarkers is urgently required for the guidance of the individualized treatment and management of BC patients. As a kind of protein that can function via interaction with target RNAs, multiple RBPs have been found to be dysregulated and relevant to the prognosis of BC patients [ 44 , 45 , 46 ]. Furthermore, the prognostic signature constructed by three RBPs has also been established in BC [ 47 ].…”

Comprehensive analysis of PPPCs family reveals the clinical significance of PPP1CA and PPP4C in breast cancer

“…This result could partially explain why the bc-GenExMiner database indicated a high rate of lymph node metastasis in patients with high PPP1CA expression. In addition, PPP1CA can bind to cyclin D1 to phosphorylate RB [ 29 ] or can dephosphorylate breast cancer susceptibility protein-1 (BRCA1) [ 30 ], all of which induce cell cycle deregulation and promote tumor cell proliferation. Therefore, inhibition of PPP1CA may play an important role in inhibiting breast cancer proliferation and metastasis.…”

RNA-binding protein p54nrb/NONO potentiates nuclear EGFR-mediated tumorigenesis of triple-negative breast cancer

“…Liu et al reported DCAF3, a novel RBP, promoted TNBC metastasis by binding to and accelerating the degradation of DTX3 [ 25 ]. Chen et al showed MCPIP1, a zinc finger RBP, suppressed the proliferation of TNBC by mediated NFIC alternative splicing [ 26 ]. To clarify the exact RBP in nuclear EGFR-mediated cancer progression, we evaluated the clinical value of those RBPs in TNBC and found NONO was significantly upregulated in TNBC and closely associated with breast cancer malignancy.…”

“…Mounting evidence has shown that RBPs are involved in various important biological processes [ 24 ]. Moreover, recent studies have identified RBPs play a critical role in TNBC [ 25 , 26 ], but the underlying mechanisms and clinical significance of the vast majority of RBPs in TNBC remain unknown. Here, we observed non-POU domain-containing octamer-binding protein (NONO, a.k.a.…”