The RNA Helicase DDX21 Activates YAP to Promote Tumorigenesis and is Transcriptionally Upregulated by β-catenin in Colorectal Cancer

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2024 Sep 16

PMID 39285230

Authors

Wenbo Tang

Yiqing Yang

Zhuoyue Fu

Weimin Xu

Weijun Ou

Fangyuan Liu

Peng Du

Chen-Ying Liu

Affiliations

Soon will be listed here.

Abstract

The RNA helicase DDX21 is vital for ribosome biogenesis and is upregulated in CRC, but the mechanism by which DDX21 is dysregulated and by which DDX21 promotes tumorigenesis in CRC remains poorly understood. Here, we showed that DDX21 is a direct transcriptional target gene of β-catenin and mediates the protumorigenic function of β-catenin in CRC. DDX21 expression is correlated with the expression and activity of β-catenin, and high DDX21 expression is associated with a poor prognosis in CRC patients. Loss of DDX21 leads to cytoplasmic translocation and decreased transcriptional activity of YAP and suppresses the proliferation and migration of CRC cells, which can be partially rescued by YAP reactivation. Importantly, by using translation elongation inhibitors and DNA intercalators, we showed that ribosomal stress upregulates DDX21 expression and induces the downregulation of LATS and the activation of YAP, probably through the ZAKα-MKK4/7-JNK axis. Overall, our study revealed the transcriptional activation mechanism of DDX21 in CRC and the activation of YAP in the ribosomal stress response, indicating the potential of combination therapy involving the induction of ribosomal stress and YAP inhibition.

Citing Articles

DDX21 Controls Cell Cycle Progression and Autophagy in Pancreatic Cancer Cells.

Leccese A, Ruta V, Panzeri V, Attili F, Spada C, Cianfanelli V Cancers (Basel). 2025; 17(4).

PMID: 40002164 PMC: 11852591. DOI: 10.3390/cancers17040570.

References

Guo X, Zhao Y, Yan H, Yang Y, Shen S, Dai X . Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev. 2017; 31(3):247-259. PMC: 5358722. DOI: 10.1101/gad.294348.116. View

Wang Y, Xu X, Maglic D, Dill M, Mojumdar K, Ng P . Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer. Cell Rep. 2018; 25(5):1304-1317.e5. PMC: 6326181. DOI: 10.1016/j.celrep.2018.10.001. View

Wang G, Lu X, Dey P, Deng P, Wu C, Jiang S . Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression. Cancer Discov. 2015; 6(1):80-95. PMC: 4707102. DOI: 10.1158/2159-8290.CD-15-0224. View

Gao H, Wei H, Yang Y, Li H, Liang J, Ye J . Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway. Oncogene. 2023; 42(21):1704-1715. PMC: 10202810. DOI: 10.1038/s41388-023-02687-6. View

Vind A, Genzor A, Bekker-Jensen S . Ribosomal stress-surveillance: three pathways is a magic number. Nucleic Acids Res. 2020; 48(19):10648-10661. PMC: 7641731. DOI: 10.1093/nar/gkaa757. View

Zhu Z, Guo Y, Liu Y, Ding R, Huang Z, Yu W . ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3-Dependent Manner. Adv Sci (Weinh). 2023; 10(32):e2303378. PMC: 10646254. DOI: 10.1002/advs.202303378. View

Meniel V, Song F, Phesse T, Young M, Poetz O, Parry L . Cited1 deficiency suppresses intestinal tumorigenesis. PLoS Genet. 2013; 9(8):e1003638. PMC: 3731217. DOI: 10.1371/journal.pgen.1003638. View

Raveux A, Stedman A, Coqueran S, Vandormael-Pournin S, Owens N, Romagnolo B . Compensation between Wnt-driven tumorigenesis and cellular responses to ribosome biogenesis inhibition in the murine intestinal epithelium. Cell Death Differ. 2020; 27(10):2872-2887. PMC: 7493937. DOI: 10.1038/s41418-020-0548-6. View

Clevers H, Nusse R . Wnt/β-catenin signaling and disease. Cell. 2012; 149(6):1192-205. DOI: 10.1016/j.cell.2012.05.012. View

10.

Codelia V, Sun G, Irvine K . Regulation of YAP by mechanical strain through Jnk and Hippo signaling. Curr Biol. 2014; 24(17):2012-7. PMC: 4160395. DOI: 10.1016/j.cub.2014.07.034. View

11.

Vind A, Snieckute G, Blasius M, Tiedje C, Krogh N, Bekker-Jensen D . ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains. Mol Cell. 2020; 78(4):700-713.e7. DOI: 10.1016/j.molcel.2020.03.021. View

12.

Zisi A, Bartek J, Lindstrom M . Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward. Cancers (Basel). 2022; 14(9). PMC: 9100539. DOI: 10.3390/cancers14092126. View

13.

Madan B, Harmston N, Nallan G, Montoya A, Faull P, Petretto E . Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis. J Clin Invest. 2018; 128(12):5620-5633. PMC: 6264740. DOI: 10.1172/JCI122383. View

14.

Song C, Hotz-Wagenblatt A, Voit R, Grummt I . SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability. Genes Dev. 2017; 31(13):1370-1381. PMC: 5580657. DOI: 10.1101/gad.300624.117. View

15.

Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B . Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015; 17(9):1218-27. PMC: 6186417. DOI: 10.1038/ncb3216. View

16.

Cargill M, Venkataraman R, Lee S . DEAD-Box RNA Helicases and Genome Stability. Genes (Basel). 2021; 12(10). PMC: 8535883. DOI: 10.3390/genes12101471. View

17.

van Riggelen J, Yetil A, Felsher D . MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010; 10(4):301-9. DOI: 10.1038/nrc2819. View

18.

Liu Y, Wang G, Yang Y, Mei Z, Liang Z, Cui A . Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial-mesenchymal transition and metastasis in a YAP-independent manner. Oncogene. 2015; 35(21):2789-800. DOI: 10.1038/onc.2015.342. View

19.

Xie J, Wen M, Zhang J, Wang Z, Wang M, Qiu Y . The Roles of RNA Helicases in DNA Damage Repair and Tumorigenesis Reveal Precision Therapeutic Strategies. Cancer Res. 2022; 82(5):872-884. DOI: 10.1158/0008-5472.CAN-21-2187. View

20.

Pelletier J, Thomas G, Volarevic S . Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer. 2017; 18(1):51-63. DOI: 10.1038/nrc.2017.104. View