Hsa_circ_0062682 Promotes Serine Metabolism and Tumor Growth in Colorectal Cancer by Regulating the miR-940/PHGDH Axis

Abstract

Colorectal cancer (CRC) is one of the most common malignancies globally. Increasing evidence indicates that circular RNAs (circRNAs) play a pivotal role in various cancers. The present study focused on exploring the role of a functionally unknown circRNA, hsa_circ_0062682 (circ_0062682), in CRC. By online analyses and experimental validations, we showed that circ_0062682 expression was aberrantly increased in CRC tissues compared with paired normal tissues. Increased expression of circ_0062682 in CRC notably correlated with a poor prognosis and advanced tumor stage. Functional experiments showed that circ_0062682 knockdown reduced CRC growth both in vitro and in vivo. Mechanistically, we revealed that circ_0062682 could sponge miR-940 and identified D-3-phosphoglycerate dehydrogenase (PHGDH), a key oxidoreductase involved in serine biosynthesis, as a novel target of miR-940. Silencing miR-940 expression could mimic the inhibitory effect of circ_0062682 knockdown on CRC proliferation. The expression of PHGDH was downregulated in circ_0062682-depleted or miR-940 overexpressing CRC cells at both the mRNA and protein levels. Circ_0062682 knockdown suppressed CRC growth by decreasing PHGDH expression and serine production via miR-940. Taken together, these data demonstrate, for the first time, that circ_0062682 promotes serine metabolism and tumor growth in CRC by regulating the miR-940/PHGDH axis, suggesting circ_0062682 as a potential novel therapeutic target for CRC.

Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma

“…By reanalysing available transcriptomic datasets of HCC patients, we identified an upregulated circRNA hsa_circ_0062682 and evaluated its oncogenic potential. Aberrant expression of hsa_circ_0062682 has previously been implicated in lung adenocarcinoma [ 66 ] and in colorectal carcinoma where it was shown to promote tumour growth and serine metabolism [ 67 ]. By performing cell-based assays we could confirm the implication of hsa_circ_0062682 in proliferation, colony formation, migration, and invasion of HCC model cell lines.…”

Mechanism underlying circRNA dysregulation in the TME of digestive system cancer

“…Moreover, circ0007031 was associated with anti-5-fu chemotherapy ( 118 ), and upregulated circ0005963 enhances glycolysis and oxaliplatin resistance to increase the size of drug-resistant tumors in vivo ( 119 ). In terms of biological function, circSLC7A6, circ-133, circEIF3K, circ0062682, circUBAP2, circ-ERBIN, circCSPP1, and circ0007031 promote cell proliferation and colony formation, and increase migration and invasion ( 112 , 113 , 116 – 118 , 120 – 122 ). CircMMP1 knockdown inhibits the growth and metastasis of CRC in vivo and suppresses the proliferation and invasion of CRC cells in vitro ( 123 ).…”

“…The one-carbon unit can regulate the proliferation of cancer cells by affecting nucleotide synthesis, methylation pathways, and redox balance ( 222 , 223 ). Circ0062682 exerts its carcinomatous functions by sponging miR-940, which targets PHGDH ( 120 ). As the first step rate-limiting enzyme in the serine biosynthetic pathway, PHGDH promotes cancer cell proliferation through overexpression in various cancers ( 224 ).…”

Noncoding RNAs as sensors of tumor microenvironmental stress

“…Mechanistically, circACC1 assembles and stabilizes the AMPK complex, ultimately increasing both glycolysis and fatty acid β-oxidation that further support colorectal cancer development [ 130 ]. Lastly, it is reported that Hsa_circ_0062682, a serum and serine starvation-induced circRNA, promotes serine metabolism and tumor growth via miR-940/PHGDH axis in colorectal cancer [ 131 ].…”