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Endoplasmic reticulum stress-induced tRNA fragmentation

ABSTRACT: Transfer RNA-derived fragments have specific biological roles. However, it is still not characterized what factors are responsible for generation of 5′-tRHs in certain conditions, such as metabolic disease and maturation of reproductive cells. Here, we report that Inositol-requiring enzyme 1α (IRE1α), a major ER stress sensor protein, cleaves specifically anticodon stem-loop region of tRNAGly(GCC) and produces 5′-tRHs. Using an RNA-seq-based approach, we identified cleavage sites in tRNAGly(GCC), generating 5′-tRHs in KGN cells (human ovarian granulosa cells) in an IRE1α-expression dependent manner. In vitro cleavage analyses further supported that IRE1α generates 5′-tRHs from tRNAGly(GCC) (5′-tRH-GlyGCC) with highly selective target discrimination. The production of 5′-tRH-GlyGCC was promoted upon endoplasmic reticulum (ER) stress, which induced IRE1α expression, in KGN cells as well as other cancer cell lines such as HeLa and HepG. In addition, transfection of synthetic 5′-tRH-GlyGCC mimics promoted survival of KGN and HeLa cells; this effect required expression of HNRNPM and HNRNPH2, which were identified as binding proteins of 5′-tRH-GlyGCC.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Granulosa Cell

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Yong-Hak Kim

LAB HEAD: Kim, Yong-Hak

PROVIDER: PXD013798 | Pride | 2024-10-30

REPOSITORIES: Pride

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Project description:Background: Prostate cancer (PCa) cells preferentially metastasize to bone at least in part by acquiring osteomimetic properties. Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome-wide mRNA expression changes in PCa cells in response to Runx2. Results: We engineered a C4-2B PCa sub-line called C4-2B/Rx2dox, in which doxycycline (Dox) treatment stimulates Runx2 expression from very low levels to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer-associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (Sox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels declined after Dox withdrawal. Conclusions: The effects of Runx2 in C4-2B/Rx2dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual downstream genes and pathways. C4-2B/Rx2dox cells were subjected to microarray gene expression analysis after one and two days of treatment with either Dox or vehicle in biological quadruplicates (a total of 16 samples).

			Action	DRS
	KH1.msf	Msf
	KH1.raw	Raw
	KH10.msf	Msf
	KH10.raw	Raw
	KH11.msf	Msf

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Endoplasmic reticulum stress-induced tRNA fragmentation

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