Circular RNA circ-DONSON facilitates gastric cancer growth and invasion via NURF complex dependent activation of transcription factor SOX4

Abstract

Background Circular RNAs (circRNAs) are a novel type of noncoding RNAs and play important roles in tumorigenesis, including gastric cancer (GC). However, the functions of most circRNAs remain poorly understood. In our study, we aimed to investigate the functions of a new circRNA circ-DONSON in GC progression. Methods The expression of circ-DONSON in gastric cancer tissues and adjacent normal tissues was analyzed by bioinformatics method, qRT-PCR, Northern blotting and in situ hybridization (ISH). The effects of circ-DONSON on GC cell proliferation, apoptosis, migration and invasion were measured by using CCK8, colony formation, EdU, immunofluorescence (IF), FACS and Transwell assays. qRT-PCR and Western blotting were utilized to validate how circ-DONSON regulates SOX4 expression. ChIP, DNA fluorescence in situ hybridization (DNA-FISH) and DNA accessibility assays were used to investigate how circ-DONSON regulates SOX4 transcription. The interaction between circ-DONSON and NURF complex was evaluated by mass spectrum, RNA immunoprecipitation (RIP), pulldown and EMSA assays. Xenograft mouse model was used to analyze the effect of circ-DONSON on GC growth in vivo. Results Elevated expression of circ-DONSON was observed in GC tissues and positively associated with advanced TNM stage and unfavorable prognosis. Silencing of circ-DONSON significantly suppressed the proliferation, migration and invasion of GC cells while promoting apoptosis. circ-DONSON was localized in the nucleus, recruited the NURF complex to SOX4 promoter and initiated its transcription. Silencing of the NURF complex subunit SNF2L, BPTF or RBBP4 similarly attenuated GC cell growth and increased apoptosis. circ-DONSON knockdown inhibited GC growth in vivo. Conclusion circ-DONSON promotes GC progression through recruiting the NURF complex to initiate SOX4 expression. Electronic supplementary material The online version of this article (10.1186/s12943-019-1006-2) contains supplementary material, which is available to authorized users.

Replisome genes regulation by antitumor miR‐101‐5p in clear cell renal cell carcinoma

“…Recently, DONSON was found to encode a novel fork protein factor and play an important role in mammalian DNA replication and genome stability. Moreover, its mutation caused microcephalic dwarfism . Previous studies showed that DONSON is a member of replisome complex and protected stalled or damaged replication forks.…”

“…Recent studies showed that expression of circular RNAs in cancer cells have participated in oncogenesis . Interestingly, overexpression of circ‐ DONSON (derived from exon 3 to exon 8 of DONSON mRNA) was detected in gastric cancer and its aberrant expression promoted gastric cancer cell aggressiveness through initiated SOX4 expression . The oncogenic roles of the circ‐ DONSON in ccRCC cells need to be investigated in the future.…”

CircDUSP16 promotes the tumorigenesis and invasion of gastric cancer by sponging miR-145-5p

“…Increasing evidence indicated that circRNAs act as potential biomarkers in patients with GC. Upregulation of circ-DON-SON, circAKT3, and circDLST [8,11,13] or downregulation of KIAA1244, circPSMC3, and circFAT1(e2) [14][15][16] is regarded as independent prognostic factors of poor prognosis in patients with GC. Herein, we identified a novel circDUSP16, and it was resistant to RNase R and localized in the cytoplasm of GC cells.…”

“…Circular RNAa (circRNAs), a new subtype of ncRNAs, have covalently closed loop structures with a back splice site between 5′-and 3′-end and exhibit higher conservativity than the corresponding linear RNAs duo to resistance to RNase R [7]. Mounting data indicated that circRNAs act critical roles in multiple molecular mechanisms including tumor biomarkers, regulating gene expression, and sponging miRNAs in cancer [8][9][10]. Circ-DONSON [8], circAGO2 [9], circAKT3 [11], circNRIP1 [12], and circDLST [13] are upregulated in GC tissues samples, and their increased expression is associated with TNM stage and poor prognosis in patients with GC [8,11,13].…”

“…Mounting data indicated that circRNAs act critical roles in multiple molecular mechanisms including tumor biomarkers, regulating gene expression, and sponging miRNAs in cancer [8][9][10]. Circ-DONSON [8], circAGO2 [9], circAKT3 [11], circNRIP1 [12], and circDLST [13] are upregulated in GC tissues samples, and their increased expression is associated with TNM stage and poor prognosis in patients with GC [8,11,13]. CircAKT3 and circDLST act as the sponges of miR-198/-502-5p to favor the tumorigenesis and cisplatin resistance in GC cells [11,13].…”