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Gene expression analysis to identify target genes of miR-150 in Burkitt lymphma cell lines

ABSTRACT: The oncogenic transcription factor MYC regulates expression of protein-coding genes, microRNAs and long non-coding RNAs. Here we show that overexpression of the MYC-repressed miR-150 severely impaired growth of Burkitt lymphoma (BL) cells. AGO2-RIP-Chip revealed two novel miR-150 targets, ZDHHC11 and ZDHHC11B, as the two most enriched genes, followed by MYB, a known miR-150 target. ZDHHC11 and ZDHHC11B encode both protein-coding and non-coding transcripts and contain a strikingly high number of miR-150 binding sites, i.e. 18 and 62, respectively. Effective targeting of ZDHHC11 and ZDHHC11B by miR-150 was confirmed by luciferase assay and for the ZDHHC11 protein by Western blot. Furthermore, we identified a circular ZDHHC11 transcript which contains the miR-150 binding site region and interacts strongly with miR-150. Knockdown of both MYB and ZDHHC11/ZDHHC11B significantly impaired growth of BL cells. Moreover, downregulation of ZDHHC11/ZDHHC11B also resulted in reduced MYB levels in BL cells. Together, our results demonstrate that elevated levels of MYB required for the high proliferative state of BL cells are ensured in two ways. First, MYC represses the tumor suppressor miR-150, which prevents its inhibitory effects on MYB expression. Second, the novel miR-150 targets ZDHHC11 and ZDHHC11B are required for maintaining high MYB levels in BL cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86432 | GEO | 2017/03/24

SECONDARY ACCESSION(S): PRJNA341858

REPOSITORIES: GEO

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Project description:Glucocorticoids (GCs) are commonly used to treat patients suffering from lymphoid malignancies i.e. leukemia and multiple myeloma. Although GCs are known to be strong inducers of apoptosis in lymphoid cells, the molecular determinants of GC therapy resistance are poorly understood. Although GC treatment triggers important changes in gene expression, few studies have addressed the regulatory role of small regulatory microRNAs (miRNAs) in GC therapy response. Only recently, aberrant microRNA expression has been linked to the development of haematological malignancies and microRNAs have become master regulators of drug resistance. We identified GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate multiple genes involved in cell cycle control, cell organization and cell death in MM1S, which remain unaffected in MM1R cells. Correspondingly, GCs selectively trigger cell death in MM1S but not in MM1R. Out of 32 microRNAs responsive to GC in MM1S cells but not in MM1R cells, mir-150 was identified as the most persistent GC responsive microRNA. Furthermore, Ingenuity Pathways Analysis (IPA) revealed that ectopic transfection of a synthetic mir-150 mimics GC therapy response in MM1S cells, associated with selective changes in mRNA levels of typical GR transactivated and transrepressed target genes. Although mir-150 largely mirrors GC responsive changes in gene expression of the transcription factor Myb, GR chaperone FKBP5, cell cycle modulator proteins (IL23A, SKP2, CDKN1A), chemokine signaling proteins (CXCR4, CX3CR1, CCL3) and mTOR/UPR stress related proteins (DDIT4, TXNIP), we also observed mir-150 selective effects on transcription factors (NR3C2 (MR), Myb, Fos, Jun, C/EBP-beta, IRF4, NFE2L1, ATF3, ATF4,), chaperone molecules HSPA8, HSP90AB1), the sodium channel SCNN1G and UPR stress proteins (TRIB3, DDIT3). Remarkably, mir-150 overexpression was not able to overcome GC therapy resistance, since we could not detect GC like effects of mir-150 in GR (NR3C1) deficient MM1R cells. Altogether GC-inducible mir-150 adds a novel complex layer of regulation for fine tuning GC specific therapeutic responses in multiple myeloma.

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Gene expression analysis to identify target genes of miR-150 in Burkitt lymphma cell lines

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