Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours

Abstract

Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours.

Multiomics-Based Signaling Pathway Network Alterations in Human Non-functional Pituitary Adenomas

“…Many studies have shown that targeting some high-frequency hub-molecules in Table 1 has achieved good results in other types of pituitary adenomas. For example, TGFβ1 is used as a novel therapeutic target to treat resistant prolactinomas (66); the microRNA-145 inhibits the activation of the mTOR signaling by targeting AKT3 to suppress the proliferation and invasion of invasive pituitary adenoma cells (67); lncRNA H19 inhibits mTORC1 by disrupting 4E-BP1/Raptor interaction in pituitary tumors (68); and MAPK Pathways act as therapeutic targets in pituitary tumors (69). Because PI3K/Akt/mTOR and ERK/MAPK signaling pathways are significantly dysregulated in NFPA, and these two essential signaling pathways are not only related to rapid proliferation and apoptosis resistance of tumor cells, but also can regulate the activities of many other pathways and then regulate tumor growth in the multiple levels.…”

LINC00511 contributes to glioblastoma tumorigenesis and epithelial‐mesenchymal transition via LINC00511/miR‐524‐5p/YB1/ZEB1 positive feedback loop

“…Studies have reported that the long non-coding RNA (lncRNA) RP11 promotes colorectal cancer cells dissemination by ZEB1 overexpression, whereas lncRNA HCCL5 could be activated by ZEB1 to promote hepatocellular carcinoma malignancy. 18,19 Among these, lncRNAs are a class of ncRNAs of more than 200 bp that have been demonstrated to be closely related to cancer progression, including tumorigenesis, 20 stemness, 21 apoptosis, 22 25 It has also been reported that LINC00511 promotes proliferation in pancreatic ductal adenocarcinoma, 26 ovarian cancer 27 and glioma. 16,17 Non-coding RNAs (ncRNAs) are transcribed genes that are not further translated into proteins and include lncRNAs, circular RNAs (circRNAs) and miRNAs, which perform vital roles in human cancers.…”

Genome-Wide Analysis and Function Prediction of Long Noncoding RNAs in Sheep Pituitary Gland Associated with Sexual Maturation

“…This indicated lncRNA H19 is a potential target for the study of invasive GHPAs [18]. LncRNA H19 could also be acted as a tumor suppressor to inhibit the pituitary tumor growth [19]. LncRNA SNHG1 activated the TGFBR2/SMAD3 and RAB11A/Wnt/β-catenin pathways to promote the progression of pituitary tumors by sponging miR-302/372/373/520 in pituitary tumor cells [20].…”