8q24 Derived ZNF252P Promotes Tumorigenesis by Driving Phase Separation to Activate C-Myc Mediated Feedback Loop

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Feb 26

PMID 40011431

Authors

Tianyu Qu

Chang Zhang

Xiyi Lu

Jiali Dai

Xuezhi He

Wei Li

Liang Han

Dandan Yin

Erbao Zhang

Affiliations

Soon will be listed here.

Abstract

As a well-known cancer risk region, the 8q24 locus is frequently amplified in a variety of solid tumors. Here we identify a pseudogene-derived oncogenic lncRNA, ZNF252P, which is upregulated in a variety of cancer types by copy number gain as well as c-Myc-mediated transcriptional activation. Mechanistically, ZNF252P binds and drives "phase separation" of HNRNPK and ILF3 protein in the nucleus and cytoplasm, respectively, to transcriptionally and posttranscriptionally activate c-Myc, thus forming a c-Myc/ZNF252P/c-Myc positive feedback loop. These findings expand the understanding of the relationship between genomic instability in the 8q24 region and tumorigenesis and clarify a regulatory mechanism involved in transcription and posttranscription from the perspective of RNA-mediated nuclear and cytoplasmic protein phase separation, which sheds light on the dialogue with the driver oncogene c-Myc. The pivotal regulatory axis of ZNF252P/c-Myc has potential as a promising biomarker and therapeutic target in cancer development.

References

Grandori C, Cowley S, James L, Eisenman R . The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol. 2000; 16:653-99. DOI: 10.1146/annurev.cellbio.16.1.653. View

Shao W, Bi X, Pan Y, Gao B, Wu J, Yin Y . Phase separation of RNA-binding protein promotes polymerase binding and transcription. Nat Chem Biol. 2021; 18(1):70-80. DOI: 10.1038/s41589-021-00904-5. View

Van Nostrand E, Pratt G, Shishkin A, Gelboin-Burkhart C, Fang M, Sundararaman B . Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat Methods. 2016; 13(6):508-14. PMC: 4887338. DOI: 10.1038/nmeth.3810. View

Recondo G, Che J, Janne P, Awad M . Targeting Dysregulation in Cancer. Cancer Discov. 2020; 10(7):922-934. PMC: 7781009. DOI: 10.1158/2159-8290.CD-19-1446. View

Shaath H, Vishnubalaji R, Elango R, Kardousha A, Islam Z, Qureshi R . Long non-coding RNA and RNA-binding protein interactions in cancer: Experimental and machine learning approaches. Semin Cancer Biol. 2022; 86(Pt 3):325-345. DOI: 10.1016/j.semcancer.2022.05.013. View

Shao S, Chang L, Sun Y, Hou Y, Fan X, Sun Y . Multiplexed sgRNA Expression Allows Versatile Single Nonrepetitive DNA Labeling and Endogenous Gene Regulation. ACS Synth Biol. 2017; 7(1):176-186. DOI: 10.1021/acssynbio.7b00268. View

Garcia-Jove Navarro M, Kashida S, Chouaib R, Souquere S, Pierron G, Weil D . RNA is a critical element for the sizing and the composition of phase-separated RNA-protein condensates. Nat Commun. 2019; 10(1):3230. PMC: 6642089. DOI: 10.1038/s41467-019-11241-6. View

Zanconato F, Cordenonsi M, Piccolo S . YAP/TAZ at the Roots of Cancer. Cancer Cell. 2016; 29(6):783-803. PMC: 6186419. DOI: 10.1016/j.ccell.2016.05.005. View

Ren D, Sun Y, Zhang D, Li D, Liu Z, Jin X . SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis. Cancer Lett. 2021; 519:277-288. DOI: 10.1016/j.canlet.2021.07.035. View

10.

Tsang S, Rainusso N, Liu M, Nomura M, Patel T, Nakahata K . LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination. Oncogene. 2022; 41(50):5373-5384. DOI: 10.1038/s41388-022-02538-w. View

11.

Wang R, Cao L, Thorne R, Zhang X, Li J, Shao F . LncRNA GIRGL drives CAPRIN1-mediated phase separation to suppress glutaminase-1 translation under glutamine deprivation. Sci Adv. 2021; 7(13). PMC: 7990344. DOI: 10.1126/sciadv.abe5708. View

12.

Lin C, Suen K, Jeffrey P, Wieteska L, Lidster J, Bao P . Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state. Mol Cell. 2022; 82(6):1089-1106.e12. PMC: 8937303. DOI: 10.1016/j.molcel.2022.02.005. View

13.

Hu X, Feng Y, Zhang D, Zhao S, Hu Z, Greshock J . A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014; 26(3):344-357. PMC: 4159613. DOI: 10.1016/j.ccr.2014.07.009. View

14.

Zhu G, Xie J, Kong W, Xie J, Li Y, Du L . Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation. Cell. 2020; 183(2):490-502.e18. PMC: 7572904. DOI: 10.1016/j.cell.2020.09.002. View

15.

Liu Y, Wang J, Nie Z, Wen Y, Jia X, Zhang L . Upregulation of ERp57 promotes clear cell renal cell carcinoma progression by initiating a STAT3/ILF3 feedback loop. J Exp Clin Cancer Res. 2019; 38(1):439. PMC: 6864981. DOI: 10.1186/s13046-019-1453-z. View

16.

Kim Y, Girard L, Giacomini C, Wang P, Hernandez-Boussard T, Tibshirani R . Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene. 2005; 25(1):130-8. DOI: 10.1038/sj.onc.1208997. View

17.

Savelyeva L, Schwab M . Amplification of oncogenes revisited: from expression profiling to clinical application. Cancer Lett. 2001; 167(2):115-23. DOI: 10.1016/s0304-3835(01)00472-4. View

18.

Jehan Z, Bavi P, Sultana M, Abubaker J, Bu R, Hussain A . Frequent PIK3CA gene amplification and its clinical significance in colorectal cancer. J Pathol. 2009; 219(3):337-46. DOI: 10.1002/path.2601. View

19.

Boija A, Klein I, Young R . Biomolecular Condensates and Cancer. Cancer Cell. 2021; 39(2):174-192. PMC: 8721577. DOI: 10.1016/j.ccell.2020.12.003. View

20.

Banani S, Lee H, Hyman A, Rosen M . Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 2017; 18(5):285-298. PMC: 7434221. DOI: 10.1038/nrm.2017.7. View