Therapeutic targeting of circ‐ CUX 1 / EWSR 1/ MAZ axis inhibits glycolysis and neuroblastoma progression

Abstract

Aerobic glycolysis is a hallmark of metabolic reprogramming in tumor progression. However, the mechanisms regulating glycolytic gene expression remain elusive in neuroblastoma (NB), the most common extracranial malignancy in childhood. Herein, we identify that CUT‐like homeobox 1 (CUX1) and CUX1‐generated circular RNA (circ‐CUX1) contribute to aerobic glycolysis and NB progression. Mechanistically, p110 CUX1, a transcription factor generated by proteolytic processing of p200 CUX1, promotes the expression of enolase 1, glucose‐6‐phosphate isomerase, and phosphoglycerate kinase 1, while circ‐CUX1 binds to EWS RNA‐binding protein 1 (EWSR1) to facilitate its interaction with MYC‐associated zinc finger protein (MAZ), resulting in transactivation of MAZ and transcriptional alteration of CUX1 and other genes associated with tumor progression. Administration of an inhibitory peptide blocking circ‐CUX1‐EWSR1 interaction or lentivirus mediating circ‐CUX1 knockdown suppresses aerobic glycolysis, growth, and aggressiveness of NB cells. In clinical NB cases, CUX1 is an independent prognostic factor for unfavorable outcome, and patients with high circ‐CUX1 expression have lower survival probability. These results indicate circ‐CUX1/EWSR1/MAZ axis as a therapeutic target for aerobic glycolysis and NB progression.

<p>Identification and Validation of MSX1 as a Key Candidate for Progestin Resistance in Endometrial Cancer</p>

“…38 In this study, high expression of has-miR-124-3p predicted worse survival, which was consistent with its effect on hepatocellular carcinoma. 39 MAZ was thought to act as a therapeutic target for aerobic glycolysis and the progression of neuroblastoma 40 and prostate cancer bone metastasis. 41 TFDP1 was involved in colon cancer stemness and cell cycle progression 42 and in the endometrium of women with deep infiltrating endometriosis (DIE).…”

CUX1, A Controversial Player in Tumor Development

“…First, elevated expression of CUX1 has been observed in many types of cancers, including colorectal cancer (67), multiple myeloma (68), uterine leiomyomas (69), highgrade breast cancer (12), pancreatic cancer (70), melanoma 71, and glioma (72); second, CUX1 expression is positively associated with poor prognosis in glioma, glioblastoma, colorectal cancer, breast cancer, and pancreatic cancer (12,61,67,72); third, mouse mammary tumor virus (MMTV) p200, p110, and p75 CUX1 transgenic mice develop late-onset mammary carcinoma (64,73); fourth, active Kras mutations, such as KRAS G12D and KRAS Q61L , have been observed in mammary carcinomas from MMTV-p200 CUX1 transgenic mice, and CUX1 can cooperate with KRAS G12V , an active Kras mutant, to promote lung tumor formation in vivo (64); fifth, CUX1 is a transcriptional target downstream of the transforming growth factor β and/or PI3K-AKT signalings and contributes to enhanced proliferation, migration/invasion, and reduced apoptosis in tumor cells (12,70). More interestingly, a very recent study has demonstrated that CUX1 can generate a circular RNA (circ-CUX1) to promote tumor progression in neuroblastoma (NB) (74). This circ-CUX1 carries exon 2 and partial intron 2 of CUX1 and is up-regulated in NB tissues and cell lines.…”

“…The levels of circ-CUX1 negatively associate with the survival probability in NB patients. Circ-CUX1 can directly interact with EWSR1 and facilitate EWSR1-MAZ interaction, resulting in transactivation of MAZ and transcriptional alteration of CUX1 and other genes associated with tumor progression (74).…”

Circular RNAs in Human Cancer

“…EIcRNAs can regulate the transcription of host gene. circCUX1 interacted with EWSR1 and facilitated EWSR1-mediated MYC-associated zinc finger protein (MAZ) transactivation, resulting in transcriptional activation of its host gene CUX1 in neuroblastoma ( 114 ).…”