Circular RNAs Regulate Glucose Metabolism in Cancer Cells

Figures & data

Figure 1 Biogenesis of circRNAs. (A) Intron cyclization: intron is cleaved from the pre-mRNA to form a ciRNA; (B) intron pairing-driven circularization: intronic complementary base-pairs bring adjacent two exons close together. The exons and introns are then spliced by spliceosomes to form circRNAs; (C) Lariat-driven circularization: this model requires covalent binding between the splicing donor and the splicing acceptor, thereby forming an exon-containing lariat.

Table 1 CircRNAs and Their Targets in the Regulation of Glucose Metabolism in Cancer

Items	Target	CircRNA	Tumor Type	Effect on Glycolysis	Type of Study	References
GLUT	GULT1	Circ0072995	Breast cancer	Up	In vitro, in vivo	[42]
		CircKLHL24	Breast Cancer	Down	In vitro, in vivo	[135]
		CircACACA	Non-small-cell lung Cancer	Up	In vitro, in vivo.	[83]
		Circ0000376,	Non-Small Cell Lung Cancer	Up	In vitro, in vivo	[136]
		Circ0002130	Non-Small Cell Lung Cancer	Up	In vitro, in vivo	[137]
		Circ100290	Oral squamous cell carcinoma	Up	In vitro	[41]
		CircKIAA0907	Oral squamous cell carcinoma	Down	In vitro, in vivo	[138]
		Circ0000140	Oral squamous cell carcinoma	Down	In vitro, in vivo	[139]
		CircFAT1	Colorectal Cancer	Down	In vitro, in vivo	[140]
		CircDENND4C	Colorectal cancer cells	Up	In vitro, in vivo	[141]
		Circ0007534	Colorectal cancer	Up	In vitro, in vivo.	[43]
		CircPTN	Glioma	Down	In vitro, in vivo	[142]
		CircTADA2A	Lung cancer	Up	In vitro, in vivo	[50]
		CircPDE5A	Neuroblastoma	Up	In vitro, in vivo.	[143]
		Circ0105346	Osteosarcoma	Up	In vitro, in vivo.	[144]
		CircPRKCI	Hepatocellular carcinoma	Down	In vitro	[145]
	GULT3	CircMYLK	Non-Small Cell Lung Cancer	Up	In vitro,	[51]
Enzymes	HK1	CircCDR1	Nasopharyngeal carcinoma	Up	In vitro, in vivo.	[26]
	HK2	CircZNF609	Nasopharyngeal carcinoma	Up	In vitro, in vivo.	[55]
		CircBICD2	Oral squamous cell carcinoma	Up	In vitro, in vivo	[147]
		CircPVT1	Oral squamous cell carcinoma	Up	In vitro, in vivo.	[54]
		CircMDM2	Oral squamous cell carcinoma	Up	In vitro, in vivo	[148]
		CircRNF20	Breast cancer	Up	In vitro, in vivo.	[57]
		Circ0069094	Breast cancer	Up	In vitro, in vivo.	[149]
		Circ0008039	Breast cancer	Up	In vitro, in vivo.	[150]
		CircRAD18	Breast Cancer	Up	In vitro, in vivo	[151]
		CircNFIX	Non-Small Cell Lung Cancer	Up	In vitro, in vivo	[152]
		Circ0008928	Non-small Cell Lung Cancer	Up	In vitro	[153]
		CircPRMT5	Hepatocellular Carcinoma	Up	In vitro, in vivo	[154]
		Circ0046599	Hepatocellular Carcinoma	Up	In vitro, in vivo	[155]
		CircZNF652	Hepatocellular Carcinoma	Up	In vitro, in vivo	[156]
		Circ009157	Hepatocellular Carcinoma	Up	In vitro	[157]
		CircTTBK2	Glioma	Up	In vitro, in vivo	[158][
		CircNFIX	Glioma	Up	In vitro, in vivo.	[58]
		Circ0001421	Lung cancer	Up	In vitro, in vivo	[159]
		Circ0080145	Chronic Myeloid Leukemia	Up	In vitro, in vivo	[160]
		Circ0001776	Endometrial cancer	Down	In vitro, in vivo	[161]
		Circ0006168	Esophageal cancer	Up	In vitro	[62]
		CircSLAMF6	Gastric cancer	Up	In vitro, in vivo	[162]
		Circ0016347	Osteosarcoma	Up	In vitro, in vivo.	[163]
		CircCDKN2B-AS1	Cervical squamous cell carcinoma	Up	In vitro, in vivo	[164]
		CircZNF609	Prostate Cancer	Up	In vitro, in vivo.	[56]
	PK	Circ0025033	Ovarian cancer	Up	In vitro, in vivo.	[63]
	PKM2	CircMAT2B	Hepatocellular carcinoma	Up	In vitro, in vivo.	[61]
		Circ0057553	Prostate Cancer	Up	In vitro, in vivo	[165]
		CircFOXM1	Melanoma	Up	In vitro, in vivo	[166]
		CircPOSTN	Glioma	Up	In vitro, in vivo.	[68]
		Circ0005963	Colorectal cancer	Up	In vitro, in vivo	[167]
	LDHA	CircECE1	Osteosarcoma	Up	In vitro, in vivo.	[82]
		Circ0056285	Osteosarcoma Cells	Up	In vitro, in vivo.	[168]
		Circ0000735	Non-small cell lung cancer	Up	In vitro, in vivo.	[169]
		CircARHGAP10	Non-small cell lung cancer	Up	In vitro, in vivo	[170]
		CircMEMO1	Non-small cell lung cancer	Up	In vitro, in vivo	[171]
		Circ0001610	Endometrial carcinoma	Up	In vitro, in vivo.	[172]
		CircSEC24A	Cutaneous Squamous Cell Carcinoma	Up	In vitro, in vivo.	[173]
		CircDUSP16	Esophageal Squamous Cell Carcinoma	Up	In vitro, in vivo.	[174]
		Circ403658	Bladder cancer	Up	In vitro, in vivo	[175]
		CircMYC	Melanoma	Up	In vitro	[176]
		Circ0136666	Colorectal Cancer	Up	In vitro, in vivo	[177]
		CircGDI2	Oral Squamous Cell Carcinoma	Down	In vitro, in vivo	[178]
		Circ0000376	Gastric cancer	Up	In vitro	[179]
		Circ0004913	Hepatocellular Carcinoma	Up	In vitro, in vivo	[180]
		CircYY1	Breast Cancer	Up	In vitro, in vivo.	[181]
		CircSMARCA5	Prostate Cancer	Up	In vitro, in vivo.	[182]
		CircPRKCI	Papillary thyroid cancer	Up	In vitro, in vivo.	[183]
PDK	PDK1	CircCNST	Osteosarcoma cells	Up	In vitro, in vivo.	[73]
		Circ0002711	Ovarian cancer	Up	In vitro, in vivo.	[74]
		CircEPHB4	Gliomas	Up	In vitro, in vivo.	[75]
	PDK2	Circ0091579	Hepatocellular carcinoma	Up	In vitro, in vivo.	[76]
	PDK4	CircCCDC66	thyroid cancer	Up	In vitro	[77]
Oncogenes	C-Myc	CircENO1	Lung adenocarcinoma	Up	In vitro, in vivo.	[87]
	ENO1	CircCUX1	Neuroblastoma	Up	In vitro, in vivo.	[90]
		CircABCB10	Breast Cancer	Up	In vitro	[69]
		CircSEMA5A	Bladder cancer	Up	In vitro, in vivo	[184]
HIF	HIF-1a	CircNRIP1	Gastric Carcinoma	Up	In vitro	[99]
		CircMAT2B	Gastric Carcinoma	Up	In vitro, in vivo	[185]
		CircDENND4C	Breast cancer	Up	In vitro, in vivo.	[98]
		CircZFR	Breast cancer	Up	In vitro, in vivo	[186]
		CircPITX1	Glioma	Up	In vitro, in vivo	[187]
		CircSEPT9	Glioma	Up	In vitro, in vivo.	[188]
		Circ03955	Pancreatic cancer	Up	In vitro, in vivo.	[189]
		CircAKT3	Lung cancer	Down	In vitro, in vivo	[190]
		CircSLC25A16	Non-small cell lung cancer	Up	In vitro, in vivo	[191]
Wnt/Snail	EMT	CircFNDC3B	Colon cancer	Down	In vitro, in vivo	[110]
		Circ0072387	Oral Squamous Cell Carcinoma	Down	In vitro, in vivo	[111]
		Circ0035483	Renal Cell Carcinoma	Up	In vitro, in vivo.	[192]
		Circ0085616	Cervical Cancer	Up	In vitro, in vivo	[193]
		Circ0001721	Osteosarcoma	Up	In vitro, in vivo	[194]
		Circ0000517	Hepatocellular carcinoma	Up	In vitro, in vivo	[195]
PI3K/AKT/mTOR		CircRHOBTB3	Ovarian cancer.	Down	In vitro	[121]
		CircHIPK3	Lung cancer	Up	In vitro, in vivo	[120]

Figure 2 CircRNAs regulate the molecules involved in glucose metabolism in cancer. CircRNAs regulate glucose uptake and glycolytic flux by modulating GLUTs and glycolic enzymes.

Figure 3 Role of CircRNA-mediated HIF and S6K/S6 pathways in glucose metabolism in tumor cells. CircRNAs can regulate HIF-1α protein synthesis and stability, thereby modulating HIF-1-mediated metabolic reprogramming. HIF-1α plays a key role in stimulating glycolic enzymes and in blocking mitochondrial activity. CircRNAs can also regulate S6K pathways. S6K may elevate oxidative phosphorylation by enhancing metabolic coupling between glycolysis and oxidative phosphorylation and increases glucose uptake and flux.

Figure 4 The ceRNA network of circRNA-miRNA-mRNA. Spherical indicate circRNA, diamond represent miRNA, and rectangles indicate mRNA.