Exosome‐derived circTFDP2 promotes prostate cancer progression by preventing PARP1 from caspase‐3‐dependent cleavage

Abstract

Background Circular RNAs (circRNAs) have been reported to play a significant role in tumorigenesis. However, the detailed function of circRNA in prostate cancer (PCa) is still largely unknown. Methods We quantified circTFDP2 expression in PCa tissues and adjacent normal tissues using quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR). Colony formation, Cell Counting Kit‐8 (CCK‐8), flow cytometry, transwell, and in vivo progression and metastasis assays were applied to reveal the proliferation and metastatic abilities of circTFDP2 in PCa cells. Mass spectrometry, RNA pulldown, RNA‐immunoprecipitation (RIP), western blotting and immunofluorescence were used for the mechanistic studies. qRT‐PCR and RIP assays were used to explore the regulatory role of eIF4A3 in the biogenesis of circTFDP2. Finally, functional assays showed the effect of circTFDP2‐containing exosomes on PCa cell progression. Results circTFDP2 was upregulated in PCa tissues compared with adjacent normal tissues. Furthermore, high circTFDP2 expression was positively correlated with the Gleason score. Functionally, circTFDP2 promoted PCa cell proliferation and metastasis both in vivo and in vitro. Mechanistically, circTFDP2 interacted with poly(ADP‐ribose) polymerase 1 (PARP1) protein in its DNA‐binding domain to prevent it from active caspase‐3‐dependent cleavage, and finally relieved PCa cells from DNA damage. In addition, RNA‐binding protein eIF4A3 can interact with the flanking region of circTFDP2 and promote the biogenesis of circTFDP2. Moreover, exosome‐derived circTFDP2 promoted PCa cell progression. Conclusions In general, our study demonstrated that circTFDP2 promoted PCa cell progression through the PARP1/DNA damage axis, which may be a promising therapeutic target for PCa.

Recent Progress on Exosomes in the Diagnosis of Prostate Cancer

“…In addition, it was reported that exosomal circRNA HIPK3 knockdown inhibited cell proliferation and metastasis in prostate cancer by regulating miR-212/BMI-1 pathway [58]. circ0081234 was inhibited is able to reduce prostate cancer tumor growth and metastasis via the miR-1/ MAP 3 K1 axis [59].…”

Exploring the interplay between PARP1 and circRNA biogenesis and function

“…We showed that PARP1 binds several types of RNAs, but due to the novelty of circRNA detection and the limitations of bioinformatic tools for their discovery, we did not probe for PARP1‐circRNA interactome. However, a recent study showed that circTFDP2 binds directly to the DNA‐binding domain of PARP1, and affecting PARP1's activity (L. Ding et al, 2023).…”

“…In competition assays, we showed that though PARP1 preferentially binds DNA, deletion of Zn1 and Zn2 DNA binding domains shifted PARP1 from a DNA binder to an RNA binder (Melikishvili et al, 2017). A recent finding however, showed that circTFDP2 binds PARP1 at the DNA binding domain (L. Ding et al, 2023). These results suggest that there could be multiple sites on PARP1 important for PARP1‐RNA and PARP1‐circRNA.…”

Cellular senescence: A potential mode of circular RNAs regulating prostate cancer

“…Plentiful studies have revealed that circRNAs are implicated in multiple biological processes of tumorigenesis and malignant progression via acting as microRNA (miRNA) sponges, RNA binding protein (RBP) molecules, transcriptional regulators, or templates for protein translations 29–34 . There are currently multiple studies demonstrating that circRNAs, as a major regulator of PCa, can influence the occurrence and progression of PCa in various ways 35–38 . However, the exploration of circRNAs' regulation in cellular senescence of PCa was limited.…”

“…[29][30][31][32][33][34] There are currently multiple studies demonstrating that circRNAs, as a major regulator of PCa, can influence the occurrence and progression of PCa in various ways. [35][36][37][38] However, the exploration of circRNAs' regulation in cellular senescence of PCa was limited.…”