Transcription Factor RFX7 Governs a Tumor Suppressor Network in Response to P53 and Stress

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2021 Jul 1

PMID 34197623

Citations 11

Authors

Luis Coronel

Konstantin Riege

Katjana Schwab

Silke Forste

David Hackes

Lena Semerau

Stephan H Bernhart

Reiner Siebert

Steve Hoffmann

Martin Fischer

Affiliations

Soon will be listed here.

Abstract

Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7's role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.

Citing Articles

Gene regulation by convergent promoters.

Wiechens E, Vigliotti F, Siniuk K, Schwarz R, Schwab K, Riege K Nat Genet. 2025; 57(1):206-217.

PMID: 39779959 PMC: 11735407. DOI: 10.1038/s41588-024-02025-w.

p53 target ANKRA2 cooperates with RFX7 to regulate tumor suppressor genes.

Schwab K, Riege K, Coronel L, Stanko C, Forste S, Hoffmann S Cell Death Discov. 2024; 10(1):376.

PMID: 39181888 PMC: 11344851. DOI: 10.1038/s41420-024-02149-2.

Pan-cancer investigation of RFX family and associated genes identifies RFX8 as a therapeutic target in leukemia.

Cui Z, Fu Y, Zhou M, Feng H, Zhang L, Ma S Heliyon. 2024; 10(15):e35368.

PMID: 39170430 PMC: 11336603. DOI: 10.1016/j.heliyon.2024.e35368.

Elucidating the chain of command: our current understanding of critical target genes for p53-mediated tumor suppression.

Indeglia A, Murphy M Crit Rev Biochem Mol Biol. 2024; 59(1-2):128-138.

PMID: 38661126 PMC: 11209770. DOI: 10.1080/10409238.2024.2344465.

A molecular mechanism for the "digital" response of p53 to stress.

Safieh J, Chazan A, Saleem H, Vyas P, Danin-Poleg Y, Ron D Proc Natl Acad Sci U S A. 2023; 120(49):e2305713120.

PMID: 38015851 PMC: 10710088. DOI: 10.1073/pnas.2305713120.

References

Manojlovic Z, Earwood R, Kato A, Stefanovic B, Kato Y . RFX7 is required for the formation of cilia in the neural tube. Mech Dev. 2014; 132:28-37. PMC: 3976564. DOI: 10.1016/j.mod.2014.02.001. View

Barbie D, Tamayo P, Boehm J, Kim S, Moody S, Dunn I . Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009; 462(7269):108-12. PMC: 2783335. DOI: 10.1038/nature08460. View

Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Iny Stein T . GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford). 2017; 2017. PMC: 5467550. DOI: 10.1093/database/bax028. View

Liu M, Dhanwada K, Birt D, Hecht S, Pelling J . Increase in p53 protein half-life in mouse keratinocytes following UV-B irradiation. Carcinogenesis. 1994; 15(6):1089-92. DOI: 10.1093/carcin/15.6.1089. View

Wang L, Wang S, Li W . RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012; 28(16):2184-5. DOI: 10.1093/bioinformatics/bts356. View

Shungin D, Winkler T, Croteau-Chonka D, Ferreira T, Locke A, Magi R . New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015; 518(7538):187-196. PMC: 4338562. DOI: 10.1038/nature14132. View

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

Weber J, de la Rosa J, Grove C, Schick M, Rad L, Baranov O . PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice. Nat Commun. 2019; 10(1):1415. PMC: 6440946. DOI: 10.1038/s41467-019-09180-3. View

Liu T, Ortiz J, Taing L, Meyer C, Lee B, Zhang Y . Cistrome: an integrative platform for transcriptional regulation studies. Genome Biol. 2011; 12(8):R83. PMC: 3245621. DOI: 10.1186/gb-2011-12-8-r83. View

10.

Jacob A, Morley M, Hawkins F, McCauley K, Jean J, Heins H . Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell. 2017; 21(4):472-488.e10. PMC: 5755620. DOI: 10.1016/j.stem.2017.08.014. View

11.

Gajiwala K, Chen H, Cornille F, Roques B, Reith W, MACH B . Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding. Nature. 2000; 403(6772):916-21. DOI: 10.1038/35002634. View

12.

Fischer B, Chelbi S, Guarda G . Regulatory Factor X 7 and its Potential Link to Lymphoid Cancers. Trends Cancer. 2020; 6(1):6-9. DOI: 10.1016/j.trecan.2019.11.001. View

13.

Cunningham F, Achuthan P, Akanni W, Allen J, Amode M, Armean I . Ensembl 2019. Nucleic Acids Res. 2018; 47(D1):D745-D751. PMC: 6323964. DOI: 10.1093/nar/gky1113. View

14.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

15.

Rogers L, Olivier A, Meyerholz D, Dupuy A . Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer. J Immunol. 2013; 190(8):4393-9. PMC: 3622230. DOI: 10.4049/jimmunol.1203227. View

16.

Kopylova E, Noe L, Touzet H . SortMeRNA: fast and accurate filtering of ribosomal RNAs in metatranscriptomic data. Bioinformatics. 2012; 28(24):3211-7. DOI: 10.1093/bioinformatics/bts611. View

17.

Emery P, Durand B, MACH B, Reith W . RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom. Nucleic Acids Res. 1996; 24(5):803-7. PMC: 145730. DOI: 10.1093/nar/24.5.803. View

18.

Speedy H, Di Bernardo M, Sava G, Dyer M, Holroyd A, Wang Y . A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat Genet. 2013; 46(1):56-60. DOI: 10.1038/ng.2843. View

19.

Hilliard A, Hilliard B, Zheng S, Sun H, Miwa T, Song W . Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. J Immunol. 2006; 177(11):8095-102. DOI: 10.4049/jimmunol.177.11.8095. View

20.

Gaviraghi M, Vivori C, Sanchez Y, Invernizzi F, Cattaneo A, Santoliquido B . Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus. EMBO J. 2018; 37(23). PMC: 6276881. DOI: 10.15252/embj.201899179. View