FOXP1 Drives Osteosarcoma Development by Repressing P21 and RB Transcription Downstream of P53

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2021 Mar 15

PMID 33716296

Citations 22

Authors

Hanjun Li

Xiuguo Han

Shengbing Yang

Yongjie Wang

Yang Dong

Tingting Tang

Affiliations

Soon will be listed here.

Abstract

Osteosarcoma has a poor prognosis, and the poor understanding of the genetic drivers of osteosarcoma hinders further improvement in therapeutic approaches. Transcription factor forkhead box P1 (FOXP1) is a crucial modulator in skeletal development and aging. Here, we determined the role and regulatory mechanisms of FOXP1 in osteosarcoma. Higher FOXP1 expression correlated with malignancy in both osteosarcoma cell lines and clinical biopsies. FOXP1 overexpression and knockdown in osteosarcoma cell lines revealed that FOXP1 promoted proliferation, tumor sphere formation, migration and invasion, and inhibited anoikis. Mechanistically, FOXP1 acted as a repressor of P21 and RB (retinoblastoma protein) transcription, and directly interacted with the tumor suppressor p53 to inhibit its activity. Extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/JNK) signaling and c-JUN/c-FOS transcription factors were found to be upstream activators of FOXP1. Moreover, FOXP1 silencing via lentivirus or adeno-associated virus (AAV)-mediated delivery of shRNA suppressed osteosarcoma development and progression in cell-derived and patient-derived xenograft animal models. Taken together, we demonstrate that FOXP1, which is transactivated by ERK/JNK-c-JUN/c-FOS, drives osteosarcoma development by regulating the p53-P21/RB signaling cascade, suggesting that FOXP1 is a potential target for osteosarcoma therapy.

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References

Gianferante D, Mirabello L, Savage S . Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy. Nat Rev Endocrinol. 2017; 13(8):480-491. DOI: 10.1038/nrendo.2017.16. View

Lin Y, Jewell B, Gingold J, Lu L, Zhao R, Wang L . Osteosarcoma: Molecular Pathogenesis and iPSC Modeling. Trends Mol Med. 2017; 23(8):737-755. PMC: 5558609. DOI: 10.1016/j.molmed.2017.06.004. View

Kansara M, Teng M, Smyth M, Thomas D . Translational biology of osteosarcoma. Nat Rev Cancer. 2014; 14(11):722-35. DOI: 10.1038/nrc3838. View

Malkin D . Germline p53 mutations and heritable cancer. Annu Rev Genet. 1994; 28:443-65. DOI: 10.1146/annurev.ge.28.120194.002303. View

Malkin D, Li F, Strong L, Fraumeni Jr J, Nelson C, Kim D . Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990; 250(4985):1233-8. DOI: 10.1126/science.1978757. View

Mirabello L, Yeager M, Mai P, Gastier-Foster J, Gorlick R, Khanna C . Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst. 2015; 107(7). PMC: 4651039. DOI: 10.1093/jnci/djv101. View

Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E . Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 2014; 7(1):104-12. PMC: 4096827. DOI: 10.1016/j.celrep.2014.03.003. View

Miller C, Aslo A, Tsay C, Slamon D, Ishizaki K, Toguchida J . Frequency and structure of p53 rearrangements in human osteosarcoma. Cancer Res. 1990; 50(24):7950-4. View

Walkley C, Qudsi R, Sankaran V, Perry J, Gostissa M, Roth S . Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes Dev. 2008; 22(12):1662-76. PMC: 2428063. DOI: 10.1101/gad.1656808. View

10.

Berman S, Calo E, Landman A, Danielian P, Miller E, West J . Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage. Proc Natl Acad Sci U S A. 2008; 105(33):11851-6. PMC: 2575280. DOI: 10.1073/pnas.0805462105. View

11.

Armesilla-Diaz A, Elvira G, Silva A . p53 regulates the proliferation, differentiation and spontaneous transformation of mesenchymal stem cells. Exp Cell Res. 2009; 315(20):3598-610. DOI: 10.1016/j.yexcr.2009.08.004. View

12.

Lengner C, Steinman H, Gagnon J, Smith T, Henderson J, Kream B . Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. J Cell Biol. 2006; 172(6):909-21. PMC: 2063734. DOI: 10.1083/jcb.200508130. View

13.

Quist T, Jin H, Zhu J, Smith-Fry K, Capecchi M, Jones K . The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse. Oncogene. 2014; 34(32):4278-84. PMC: 4411188. DOI: 10.1038/onc.2014.354. View

14.

Hansen M, Koufos A, Gallie B, Phillips R, Fodstad O, BROGGER A . Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Proc Natl Acad Sci U S A. 1985; 82(18):6216-20. PMC: 391023. DOI: 10.1073/pnas.82.18.6216. View

15.

Wadayama B, Toguchida J, Shimizu T, Ishizaki K, Sasaki M, Kotoura Y . Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res. 1994; 54(11):3042-8. View

16.

Fittall M, Mifsud W, Pillay N, Ye H, Strobl A, Verfaillie A . Recurrent rearrangements of FOS and FOSB define osteoblastoma. Nat Commun. 2018; 9(1):2150. PMC: 5984627. DOI: 10.1038/s41467-018-04530-z. View

17.

Wang Z, Liang J, Schellander K, Wagner E, Grigoriadis A . c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Cancer Res. 1995; 55(24):6244-51. View

18.

Papachristou D, Batistatou A, Sykiotis G, Varakis I, Papavassiliou A . Activation of the JNK-AP-1 signal transduction pathway is associated with pathogenesis and progression of human osteosarcomas. Bone. 2003; 32(4):364-71. DOI: 10.1016/s8756-3282(03)00026-7. View

19.

Perry J, Kiezun A, Tonzi P, Van Allen E, Carter S, Baca S . Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A. 2014; 111(51):E5564-73. PMC: 4280630. DOI: 10.1073/pnas.1419260111. View

20.

Behjati S, Tarpey P, Haase K, Ye H, Young M, Alexandrov L . Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat Commun. 2017; 8:15936. PMC: 5490007. DOI: 10.1038/ncomms15936. View