N6-methyladenosine modification of circ_0003215 suppresses the pentose phosphate pathway and malignancy of colorectal cancer through the miR-663b/DLG4/G6PD axis

Abstract

Circular RNAs (circRNAs) are a recently discovered kind of regulatory RNAs that have emerged as critical biomarkers of various types of cancers. Metabolic reprogramming has gradually been identified as a distinct hallmark of cancer cells. The pentose phosphate pathway (PPP) plays an indispensable role in satisfying the bioenergetic and biosynthetic demands of cancer cells. However, little is known about the role of circRNAs and PPP in colorectal cancer (CRC). The novel circ_0003215 was identified at low levels in CRC and was negatively correlated with larger tumor size, higher TNM stage, and lymph node metastasis. The decreased level of circ_0003215 was resulted from the RNA degradation by m6A writer protein YTHDF2. A series of functional assays demonstrated that circ_0003215 inhibited cell proliferation, migration, invasion, and CRC tumor metastasis in vivo and in vitro. Moreover, circ_0003215 regulated the expression of DLG4 via sponging miR-663b, thereby inducing the metabolic reprogramming in CRC. Mechanismly, DLG4 inhibited the PPP through the K48-linked ubiquitination of glucose-6-phosphate dehydrogenase (G6PD). Taken together, we have identified m6A-modified circ_0003215 as a novel regulator of metabolic glucose reprogramming that inhibited the PPP and the malignant phenotype of CRC via the miR-663b/DLG4/G6PD axis.

m6A modification on the fate of colorectal cancer: functions and mechanisms of cell proliferation and tumorigenesis

“…Recently, the tumor-suppressing function of circ0003215 in CRC proliferation, invasion, and migration has been demonstrated. Importantly, YTHDF2 promotes the RNA degradation of circ0003215 (78). The above studies highlight the important roles of YTHDF2 in promoting CRC proliferation and tumorigenesis.…”

The p52-ZER6/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway

“…Meanwhile, inhibition of G6PD can lead to accumulation of reactive oxygen species, induce endoplasmic reticulum stress, and slow the growth and migration of cancer cells [ 9 , 37 ]. G6PD ubiquitination inhibits the PPP pathway and the malignant phenotype of tumors [ 38 ], reflecting its importance in PPP regulation and subsequent tumorigenesis. Interestingly, we show here that the p52-ZER6-mediated regulation of G6PD, and subsequently the PPP, is independent of p53.…”

“…Quantification data are expressed as mean ± SD (n = 3, unless otherwise indicated). shp52: shRNA expression vector targeting p52-ZER6; pcCon: pcEF9-Puro; pcp52: p52-ZER6 overexpression vector; **P < 0.01; ***P < 0.001. phenotype of tumors [38], reflecting its importance in PPP regulation and subsequent tumorigenesis. Interestingly, we show here that the p52-ZER6-mediated regulation of G6PD, and subsequently the PPP, is independent of p53.…”

Biological functions, mechanisms, and clinical significance of circular RNA in colorectal cancer

“…In a recent study, Chen B et al. ( 121 ) reported the down-regulation of circ_0003215 in CRC, which was negatively correlated with tumor size, TNM stage, and lymph node metastasis. The authors found that the decrease in circ_0003215 level was due to the RNA degradation by m6A read-write protein YTHDF2.…”