circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity

Abstract

Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.

ALKBH3 partner ASCC3 mediates P-body formation and selective clearance of MMS-induced 1-methyladenosine and 3-methylcytosine from mRNA

“…Very recently, TRIM25 was shown to ubiquitinylate the m 6 A readers IGF2BP1/2/3 and mediate their degradation. This was promoted by binding of the IGF2BPs to m 6 A-modified circular RNA circNDUFB2 and was dependent on the RNA-binding motif in TRIM25 [ 83 ]. To what extent methylated ribonucleosides modulates RNA binding and E3 ligase activity of TRIM25 itself is unknown, but such studies are warranted given known strategies used by viruses to modulate their RNA methylation pattern to avoid host immune responses [ 84 ].…”

hsa_circ_0008234 inhibits the progression of lung adenocarcinoma by sponging miR-574-5p

“…Microarray data were downloaded from the GEO database 35 , including GSE112214 and GSE158695 36 . Then the original microarray data were analyzed with GEO2R.…”

The Role of N6-Methyladenosine Modified Circular RNA in Pathophysiological Processes

“…CircNDUFB2 acts as a scaffold of tripartite motif containing 25 and IGF2BPs to form a ternary complex, which promotes the degradation of IGF2BPs and inhibits the growth and metastasis of NSCLC cells. Furthermore, m 6 A-modified circNDUFB2 can enhance this effect 139 . In addition, circNDUFB2 recognized by RIG-I can active RIG-I-MAVS signaling cascades, thereby recruiting immune cells into the tumor microenvironment.…”

“…In addition, circNDUFB2 recognized by RIG-I can active RIG-I-MAVS signaling cascades, thereby recruiting immune cells into the tumor microenvironment. Apart from enhancing IGF2BPs stability, the down-regulated circNDUFB2 in NSCLC also leads to immune evasion and promotes tumor progression 139 .…”