A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53

Abstract

Long noncoding RNAs (lncRNA) have been associated with various types of cancer; however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression, respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA-G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression. A cytosolic lncRNA functions as a tumor suppressor by activating the p53 pathway. .

Rasputin a decade on and more promiscuous than ever? A review of G3BPs

“…Facilitates viral replication and assembly. [105,113] U. Alam, D. Kennedy BBA -Molecular Cell Research 1866 (2019) 360-370 activity of the p53 signalling pathway [43]. Regardless of their mechanism of action, both G3BP proteins inhibit p53 functions and hence play an accessory role in tumorigenesis.…”

“…The interaction between G3BP2 and MDM2 compromises its ability to ubiquitinate p53 and the subsequent degradation of p53 by the proteasome [42]. A cytoplasmic lncRNA, P53RRA, interacts with the RRM domain (also responsible for the interaction of G3BP1 with p53) of G3BP1 in the cytoplasm via nucleotides 1 and 871 and this interaction displaces p53 from G3BP1-complex, subsequently retaining p53 in the nucleus, inducing cell cycle arrest and cell death [43]. P53RRA also increases the levels of MDM2 and p21 (which is a direct target of p53), showing that P53RRA promotes the…”

LUCAT1 promotes colorectal cancer tumorigenesis by targeting the ribosomal protein L40‐MDM2‐p53 pathway through binding with UBA52

“…For instance, lncRNA‐hPVT1 promotes cell proliferation, cell cycling, and stem cell‐like properties in hepatocellular carcinoma cells through binding to NOP2 and enhancing its stability . P53RRA lncRNA induces cell cycle arrest, apoptosis, and ferroptosis by binding with RAS GTPase‐activating protein‐binding protein 1, resulting in p53 retention in the nucleus . In this regard, we undertook ChiRP and mass spectrometry followed by RIP and identified UBA52 as a binding protein to LUCAT1 .…”

“…16 In addition to lung cancer, LUCAT1 has also been reported to be involved in esophageal cancer, renal cell carcinoma, and cisplatin-resistant ovarian cancer. 17 27 In this regard, we undertook ChiRP and mass spectrometry followed by RIP and identified UBA52 as a binding protein to LUCAT1. UBA52, which is located on chromosome 19, is a hybrid gene encoding a fusion protein comprising ubiquitin at the N-terminus and RPL40 at the C-terminus.…”

Long noncoding RNA MALAT1 regulates HDAC4‐mediated proliferation and apoptosis via decoying of miR‐140‐5p in osteosarcoma cells

“…Accumulating evidence has shown that lncRNAs play vital roles in multiple biological processes including proliferation, apoptosis, angiogenesis, drug resistance, and metastasis in various malignant tumors. [34][35][36][37][38] MALAT1 is a highly conserved lncRNA that was originally identified and is highly expressed in non-small-cell lung cancer. 39 MALAT1 presented diverse regulative functions on multiple malignant tumors including OS.…”