Linc-RoR promotes c-Myc expression through hnRNP I and AUF1

Abstract

Linc-RoR was originally identified to be a regulator for induced pluripotent stem cells in humans and it has also been implicated in tumorigenesis. However, the underlying mechanism of Linc-RoR-mediated gene expression in cancer is poorly understood. The present study demonstrates that Linc-RoR plays an oncogenic role in part through regulation of c-Myc expression. Linc-RoR knockout (KO) suppresses cell proliferation and tumor growth. In particular, Linc-RoR KO causes a significant decrease in c-Myc whereas re-expression of Linc-RoR in the KO cells restores the level of c-Myc. Mechanistically, Linc-RoR interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) I and AU-rich element RNA-binding protein 1 (AUF1), respectively, with an opposite consequence to their interaction with c-Myc mRNA. While Linc-RoR is required for hnRNP I to bind to c-Myc mRNA, interaction of Linc-RoR with AUF1 inhibits AUF1 to bind to c-Myc mRNA. As a result, Linc-RoR may contribute to the increased stability of c-Myc mRNA. Although hnRNP I and AUF1 can interact with many RNA species and regulate their functions, with involvement of Linc-RoR they would be able to selectively regulate mRNA stability of specific genes such as c-Myc. Together, these results support a role for Linc-RoR in c-Myc expression in part by specifically enhancing its mRNA stability, leading to cell proliferation and tumorigenesis.

The Emerging Roles of Long Noncoding RNA ROR (lincRNA-ROR) and its Possible Mechanisms in Human Cancers

“…What's more, in nasopharyngeal carcinoma, linc-ROR played an important role in the progression of NPC and the mechanism by which NPC resists chemotherapy might be that linc-ROR suppress p53 signal pathway [76]. Similar to this pathway, the linc-ROR also plays an oncogenic role in regulating the c-Myc (enhancing its mRNA stability) by interacting with hnRNP I and AU-rich element RNA-binding protein 1 (AUF1) [77,78]. Moreover, the nuclear factor-crythroid 2-related factor (NRF2), which is activated under high cellular stress and is well established as a master regulator in cellular defensing against chemical carcinogenesis [79,80], directly binding linc-ROR promoter and represses its expression [81].…”

“…So, p53, NRF2, linc-ROR and c-Myc may form a regulatory network upon DNA damage, the high expression of p53 inhibits the activation of NRF2, which leading to the upregulation of linc-ROR, as a result, the high expression of linc-ROR can supress the p53 level, at the same time inhibit the expression of c-Myc by interacting with hnRNP I and AUF1 [74,77,81]. This forms a feeback loop which confirms the importance of linc-ROR in playing an oncogenic role.…”

Endogenous retroviral promoter exaptation in human cancer

“…Evidence suggests it acts as a microRNA sponge of miR-145, which is a repressor of the core pluripotency transcription factors Oct4, Nanog and Sox2 [146]. Several recent studies have reported an oncogenic role for Linc-ROR in different cancers by sponging miR-145 [147–149] or through other mechanisms [150, 151]. …”

Linc‐RoR promotes proliferation, migration, and invasion via the Hippo/YAP pathway in pancreatic cancer cells

“…28 Linc-RoR functions as a decoy oncogenic RNA to impede the recruitment of G9A methyltransferase, abolishing histone H3K9 modification of the TESC promoter to promote tumor development. 29 After DNA damage, the level of p53 that can suppress tumor is noticeably increased; this increase is regulated in various ways, including translational control. 29 After DNA damage, the level of p53 that can suppress tumor is noticeably increased; this increase is regulated in various ways, including translational control.…”