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How a Circular RNA May Suppress Bladder Cancer Progression

By: Julia Fiederlein Cipriano, MS
Posted: Tuesday, January 2, 2024

According to Bo Xie, MD, of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, and colleagues, in human bladder cancer, the circular RNA circXRN2 appears to suppress histone 3 lysine 18 (H3K18) lactylation–driven tumor progression via the activation of the Hippo signaling pathway. Their findings, which were published in the journal Molecular Cancer, may contribute to the discovery of new molecular targets and therapeutic strategies in this clinical context.

“With the updating and advancement of high-throughput sequencing and molecular biologic technologies, noncoding RNAs have exerted emerging roles in various physiologic and pathologic processes,” the investigators remarked. “Our findings provide an original molecular mechanism of circular RNA and expand our understanding of the Hippo pathway and histone lactylation.”

After confirming circXRN2 as the research object via RNA immunoprecipitation and high-throughput sequencing, the investigators conducted several laboratory analyses to explore the underlying roles and molecular mechanisms of this circular RNA in bladder cancer. Their experiments revealed aberrant downregulation of circXRN2 in diseased bladder tissues and cell lines. In both in vitro and in vivo models, circXRN2 appeared to inhibit the proliferation and migration of tumor cells. CircXRN2 was also found to serve as a negative regulator of glycolysis and lactate production.

Mechanistically, circXRN2 seemed to protect the LATS1 protein from speckle-type POZ (SPOP)-mediated ubiquitylation and degradation by binding to the SPOP degron; the investigators reported subsequent activation of the Hippo signaling pathway. This regulatory axis was seen to further modulate tumor progression via the inhibition of H3K18 lactylation and oncogene LCN2 expression.  

Disclosure: The study authors reported no conflicts of interest.


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