The functional interplay of lncRNA EGOT and HuR regulates hypoxia‐induced autophagy in renal tubular cells

Abstract

Autophagy, an important cellular homeostatic mechanism regulates cell survival under stress and protects against acute kidney injury. However, the role of long noncoding RNA (lncRNA) in autophagy regulation in renal tubular cells (HK‐2) is unclear. The study was aimed to understand the importance of lncRNA in hypoxia‐induced autophagy in HK‐2 cells. LncRNA eosinophil granule ontogeny transcript (EGOT) was identified as autophagy‐associated lncRNA under hypoxia. The lncRNA EGOT expression was significantly downregulated in renal tubular cells during hypoxia‐induced autophagy. Gain‐ and loss‐of‐EGOT functional studies revealed that EGOT overexpression reduced autophagy by downregulation of ATG7, ATG16L1, LC3II expressions and LC 3 puncta while EGOT knockdown reversed the suppression of autophagy. Importantly, RNA‐binding protein, (ELAVL1)/Hu antigen R (HuR) binds and stabilizes the EGOT expression under normoxia and ATG7/16L1 expressions under hypoxia. Furthermore, HuR mediated stabilization of ATG7/16L1 expressions under hypoxia causes a decline in EGOT levels and thereby promotes autophagy. Altogether, the study first reveals the functional interplay of lncRNA EGOT and HuR on the posttranscriptional regulation of the ATG7/16L1 expressions. Thus, the HuR/EGOT/ATG7/16L1 axis is crucial for hypoxia‐induced autophagy in renal tubular cells.

Non-Coding RNAs in Kidney Diseases: The Long and Short of Them

“…In cultured tubular cells, upregulation of the lncRNA EGOT diminished hypoxia/reoxygenation mediated autophagy via interaction with the RNA-binding protein Hu antigen R (HuR) and further regulation of the ATG7/16L1 expressions [ 55 ]. LncRNA GAS5 was induced by I/R injury, promoting renal apoptosis by regulation of the miR-21/TSP-1 axis [ 55 ].…”

“…In cultured tubular cells, upregulation of the lncRNA EGOT diminished hypoxia/reoxygenation mediated autophagy via interaction with the RNA-binding protein Hu antigen R (HuR) and further regulation of the ATG7/16L1 expressions [ 55 ]. LncRNA GAS5 was induced by I/R injury, promoting renal apoptosis by regulation of the miR-21/TSP-1 axis [ 55 ]. The lncRNA LINC00520 was upregulated in I/R injured rats and in hypoxic tubular epithelial cells, being associated with a reduction of miR-27b and increased levels of the Oncostatin M receptor (OSMR) [ 56 ].…”

Long Non-Coding RNAs in Biliary Tract Cancer—An Up-to-Date Review

“…Several studies demonstrate that stress tolerance, which is induced through cytoprotective autophagy, can contribute to resistance against chemotherapeutics [203,204]. Regulation of autophagy involves lncRNAs [64,[205][206][207] which might also contribute to the development of chemoresistance [64]-an aspect that is especially interesting regarding BTC as BTC cells are often highly chemoresistant [64,208,209].…”

The long non-coding RNA EGOT promotes pancreatic cancer progression by sequestering miR-214 to derepress PLS3 expression

“…The lncRNA EGOT is encoded on chromosome 3p26.1 in humans, and is expressed in mature eosinophils owing to its documented role as a regulator of eosinophil development [12] . Interactions between EGOT and HuR have been shown to control hypoxia-induced autophagy in renal tubular cells [13] , and aberrant EGOT expression has also been detected in breast and kidney tumor cells [14,15] . By promoting ITPR1 upregulation via RNA-RNA and RNA-protein interactions, EGOT has also been shown to increase paclitaxel cytotoxicity [16] .…”