vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-82vavilov-4802Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYИнтерактом белка HOXB13 в клетках рака простаты: биохимические и функциональные взаимодействия между транскрипционными факторами HOXB13 и TBX3HOXB13 interactome in prostate cancer cells: biochemical and functional interactions between the transcription factors HOXB13 and TBX3ЕрохинМ. М.ErokhinM. M.

 Москва 

 Moscow 

yermaxbio@yandex.ruКозельчукН. Я.KozelchukN. Y.

 Москва 

 Moscow 

ЗиганшинР. Х.ZiganshinR. H.

 Москва 

 Moscow 

ТатарскийВ. В.TatarskiyV. V.

 Москва 

 Moscow 

ЧетверинаД. А.ChetverinaD. A.

 Москва 

 Moscow 

daria.chetverina@gmail.comИнститут биологии гена Российской академии наукРоссияInstitute of Gene Biology of the Russian Academy of SciencesRussian FederationИнститут биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова Российской академии наукРоссияShemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesRussian Federation202509102025296744752Copyright © Ерохин М.М., Козельчук Н.Я., Зиганшин Р.Х., Татарский В.В., Четверина Д.А., 20252025Ерохин М.М., Козельчук Н.Я., Зиганшин Р.Х., Татарский В.В., Четверина Д.А.Erokhin M.M., Kozelchuk N.Y., Ziganshin R.H., Tatarskiy V.V., Chetverina D.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4802

Транскрипционные факторы относятся к одной из главных групп белков, подавление активности которых приводит к остановке роста опухолей. В различных типах рака экспрессируется определенный набор транскрипционных факторов, которые создают и поддерживают специфические паттерны экспрессии генов. В клетках рака простаты ключевым транскрипционным регулятором является белок HOXB13 (Homeobox B13). Известно, что HOXB13 – важный регулятор эмбрионального развития и терминальной клеточной дифференцировки. Он регулирует транскрипцию многих генов в нормальных и трансформированных клетках простаты, а также способен действовать как пионерный фактор, который открывает хроматин в регуляторных областях генов. Однако данных о белковых партнерах и функциях HOXB13 в клетках рака простаты очень мало. В настоящей работе мы провели поиск белковых партнеров HOXB13 методом иммуноаффинной очистки с последующим высокопроизводительным масс-спектрометрическим анализом (IP/LC-MS), используя в качестве модели клеточную линию рака простаты PC-3. Было обнаружено, что основными партнерами HOXB13 являются транскрипционные факторы с разными типами ДНК-связывающих доменов, в том числе белки TBX3, TBX2, ZFHX4, ZFHX3, RUNX1, NFAT5. С помощью ресурса DepMap мы показали, что один из установленных партнеров, белок TBX3, как и HOXB13, критически важен для роста и пролиферации клеточных линий рака простаты in vitro. Анализ отдельных клеточных линий рака простаты выявил, что нокаут обоих генов, HOXB13 и TBX3, приводит к гибели одних и тех же линий: VCaP, LNCaP (clone FGC), PC-3 и 22Rv1. Таким образом, HOXB13 и TBX3 могут совместно рассматриваться как потенциальные мишени для создания специфических ингибиторов, подавляющих рост клеток рака простаты.

Transcription factors represent one of the major groups of proteins, whose suppression leads to tumor growth arrest. Different types of cancer express a specific set of transcription factors that create and maintain unique patterns of gene expression. In prostate cancer cells, one of the key transcriptional regulators is the HOXB13 (Homeobox B13) protein. HOXB13 is known to be an important regulator of embryonic development and terminal cell differentiation. HOXB13 regulates the transcription of many genes in normal and transformed prostate cells and is also capable of acting as a pioneer factor that opens chromatin in the regulatory regions of genes. However, little is known about the protein partners and functions of HOXB13 in prostate cells. In the present study, we searched for protein partners of HOXB13 by immunoaffinity purification followed by high-throughput mass spectrometric analysis (IP/LC-MS) using the PC-3 prostate cancer cell line as a model. The main partners of HOXB13 were found to be transcription factors with different types of DNA-binding domains, including the TBX3, TBX2, ZFHX4, ZFHX3, RUNX1, NFAT5 proteins. Using the DepMap resource, we have shown that one of the identified partners, the TBX3 protein is as critical for the growth and proliferation of prostate cancer cell lines in vitro as HOXB13. Analysis of individual prostate cancer cell lines revealed that knockout of both genes, HOXB13 and TBX3, leads to the death of the same lines: VCaP, LNCaP (clone FGC), PC-3 and 22Rv1. Thus, HOXB13 and TBX3 can be considered together as potential targets for the development of specific inhibitors that suppress prostate cancer cell growth.

рак простатытранскрипционные факторырегуляция транскрипцииHOXB13TBX3TBX2ZFHX4ZFHX3RUNX1NFAT5prostate cancertranscription factorsregulation of transcriptionHOXB13TBX3TBX2ZFHX4ZFHX3RUNX1NFAT5The study was supported by Russian Science Foundation grant No. 20-74-10099ReferencesAdashek J.J., Leonard A., Roszik J., Menta A.K., Genovese G., Subbiah V., Msaouel P. Cancer genetics and therapeutic opportunities in urologic practice. Cancers (Basel). 2020;12(3):710. doi 10.3390/cancers12030710Adashek J.J., Leonard A., Roszik J., Menta A.K., Genovese G., Subbiah V., Msaouel P. Cancer genetics and therapeutic opportunities in urologic practice. Cancers (Basel). 2020;12(3):710. doi 10.3390/cancers12030710Bartha Á., Győrffy B. TNMplot.com: a web tool for the comparison of gene expression in normal, tumor and metastatic tissues. Int J Mol Sci. 2021;22(5):2622. doi 10.3390/ijms22052622Bartha Á., Győrffy B. TNMplot.com: a web tool for the comparison of gene expression in normal, tumor and metastatic tissues. Int J Mol Sci. 2021;22(5):2622. doi 10.3390/ijms22052622Bouhlel M.A., Lambert M., David-Cordonnier M.-H. Targeting transcription factor binding to DNA by competing with DNA binders as an approach for controlling gene expression. Curr Top Med Chem. 2015;15(14):1323-1358. doi 10.2174/1568026615666150413154713Bouhlel M.A., Lambert M., David-Cordonnier M.-H. Targeting transcription factor binding to DNA by competing with DNA binders as an approach for controlling gene expression. Curr Top Med Chem. 2015;15(14):1323-1358. doi 10.2174/1568026615666150413154713Bushweller J.H. Targeting transcription factors in cancer – from undruggable to reality. Nat Rev Cancer. 2019;19(11):611-624. doi 10.1038/s41568-019-0196-7Bushweller J.H. Targeting transcription factors in cancer – from undruggable to reality. Nat Rev Cancer. 2019;19(11):611-624. doi 10.1038/s41568-019-0196-7Cai Q., Wang X., Li X., Gong R., Guo X., Tang Y., Yang K., Niu Y., Zhao Y. Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget. 2015;6(39):42312-42321. doi 10.18632/oncotarget.5994Cai Q., Wang X., Li X., Gong R., Guo X., Tang Y., Yang K., Niu Y., Zhao Y. Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget. 2015;6(39):42312-42321. doi 10.18632/oncotarget.5994Cao Q., Wang X., Zhao M., Yang R., Malik R., Qiao Y., Poliakov A., … Feng F.Y., Kalantry S., Qin Z.S., Dhanasekaran S.M., Chinnaiyan A.M. The central role of EED in the orchestration of polycomb group complexes. Nat Commun. 2014;5:3127. doi 10.1038/ncomms4127Cao Q., Wang X., Zhao M., Yang R., Malik R., Qiao Y., Poliakov A., … Feng F.Y., Kalantry S., Qin Z.S., Dhanasekaran S.M., Chinnaiyan A.M. The central role of EED in the orchestration of polycomb group complexes. Nat Commun. 2014;5:3127. doi 10.1038/ncomms4127Chetverina D., Vorobyeva N.E., Mazina M.Y., Fab L.V., Lomaev D., Golovnina A., Mogila V., Georgiev P., Ziganshin R.H., Erokhin M. Comparative interactome analysis of the PRE DNA-binding factors: purification of the Combgap-, Zeste-, Psq-, and Adf1-associated proteins. Cell Mol Life Sci. 2022;79(7):353. doi 10.1007/s00018-022-04383-2Chetverina D., Vorobyeva N.E., Mazina M.Y., Fab L.V., Lomaev D., Golovnina A., Mogila V., Georgiev P., Ziganshin R.H., Erokhin M. Comparative interactome analysis of the PRE DNA-binding factors: purification of the Combgap-, Zeste-, Psq-, and Adf1-associated proteins. Cell Mol Life Sci. 2022;79(7):353. doi 10.1007/s00018-022-04383-2Chetverina D., Vorobyeva N.E., Gyorffy B., Shtil A.A., Erokhin M. Analyses of genes critical to tumor survival reveal potential ‘supertargets’: focus on transcription. Cancers (Basel). 2023;15(11):3042. doi 10.3390/cancers15113042Chetverina D., Vorobyeva N.E., Gyorffy B., Shtil A.A., Erokhin M. Analyses of genes critical to tumor survival reveal potential ‘supertargets’: focus on transcription. Cancers (Basel). 2023;15(11):3042. doi 10.3390/cancers15113042Crona D.J., Whang Y.E. Androgen receptor-dependent and -independent mechanisms involved in prostate cancer therapy resistance. Cancers (Basel). 2017;9(6):67. doi 10.3390/cancers9060067Crona D.J., Whang Y.E. Androgen receptor-dependent and -independent mechanisms involved in prostate cancer therapy resistance. Cancers (Basel). 2017;9(6):67. doi 10.3390/cancers9060067Erokhin M., Georgiev P., Chetverina D. Drosophila DNA-binding proteins in polycomb repression. Epigenomes. 2018;2(1):1. doi 10.3390/epigenomes2010001Erokhin M., Georgiev P., Chetverina D. Drosophila DNA-binding proteins in polycomb repression. Epigenomes. 2018;2(1):1. doi 10.3390/epigenomes2010001Ewing C.M., Ray A.M., Lange E.M., Zuhlke K.A., Robbins C.M., Tembe W.D., Wiley K.E., … Montie J.E., Xu J., Carpten J.D., Isaacs W.B., Cooney K.A. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 2012;366(2):141-149. doi 10.1056/NEJMoa1110000Ewing C.M., Ray A.M., Lange E.M., Zuhlke K.A., Robbins C.M., Tembe W.D., Wiley K.E., … Montie J.E., Xu J., Carpten J.D., Isaacs W.B., Cooney K.A. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 2012;366(2):141-149. doi 10.1056/NEJMoa1110000Feng Y., Zhang T., Wang Y., Xie M., Ji X., Luo X., Huang W., Xia L. Homeobox genes in cancers: from carcinogenesis to recent therapeutic intervention. Front Oncol. 2021;11:770428. doi 10.3389/fonc.2021.770428Feng Y., Zhang T., Wang Y., Xie M., Ji X., Luo X., Huang W., Xia L. Homeobox genes in cancers: from carcinogenesis to recent therapeutic intervention. Front Oncol. 2021;11:770428. doi 10.3389/fonc.2021.770428Goldman M.J., Craft B., Hastie M., Repečka K., McDade F., Kamath A., Banerjee A., Luo Y., Rogers D., Brooks A.N., Zhu J., Haussler D. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020;38(6):675-678. doi 10.1038/s41587-020-0546-8Goldman M.J., Craft B., Hastie M., Repečka K., McDade F., Kamath A., Banerjee A., Luo Y., Rogers D., Brooks A.N., Zhu J., Haussler D. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020;38(6):675-678. doi 10.1038/s41587-020-0546-8Hagenbuchner J., Ausserlechner M.J. Targeting transcription factors by small compounds – current strategies and future implications. Biochem Pharmacol. 2016;107:1-13. doi 10.1016/j.bcp.2015.12.006Hagenbuchner J., Ausserlechner M.J. Targeting transcription factors by small compounds – current strategies and future implications. Biochem Pharmacol. 2016;107:1-13. doi 10.1016/j.bcp.2015.12.006Hankey W., Chen Z., Wang Q. Shaping chromatin states in prostate cancer by pioneer transcription factors. Cancer Res. 2020;80(12): 2427-2436. doi 10.1158/0008-5472.CAN-19-3447Hankey W., Chen Z., Wang Q. Shaping chromatin states in prostate cancer by pioneer transcription factors. Cancer Res. 2020;80(12): 2427-2436. doi 10.1158/0008-5472.CAN-19-3447Hayward S.W., Dahiya R., Cunha G.R., Bartek J., Deshpande N., Narayan P. Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1. In Vitro Cell Dev Biol Anim. 1995;31(1):14-24. doi 10.1007/BF02631333Hayward S.W., Dahiya R., Cunha G.R., Bartek J., Deshpande N., Narayan P. Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1. In Vitro Cell Dev Biol Anim. 1995;31(1):14-24. doi 10.1007/BF02631333Hubert K.A., Wellik D.M. Hox genes in development and beyond. Development. 2023;150(1):dev192476. doi 10.1242/dev.192476Hubert K.A., Wellik D.M. Hox genes in development and beyond. Development. 2023;150(1):dev192476. doi 10.1242/dev.192476Hwang J.H., Arafeh R., Seo J.-H., Baca S.C., Ludwig M., Arnoff T.E., Sawyer L., … Kregel S., Van Allen E.M., Drake J.M., Freedman M.L., Hahn W.C. CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies. eLife. 2022;11:e73223. doi 10.7554/eLife.73223Hwang J.H., Arafeh R., Seo J.-H., Baca S.C., Ludwig M., Arnoff T.E., Sawyer L., … Kregel S., Van Allen E.M., Drake J.M., Freedman M.L., Hahn W.C. CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies. eLife. 2022;11:e73223. doi 10.7554/eLife.73223Jolma A., Yan J., Whitington T., Toivonen J., Nitta K.R., Rastas P., Morgunova E., … Hughes T.R., Lemaire P., Ukkonen E., Kivioja T., Taipale J. DNA-binding specificities of human transcription factors. Cell. 2013;152(1-2):327-339. doi 10.1016/j.cell.2012.12.009Jolma A., Yan J., Whitington T., Toivonen J., Nitta K.R., Rastas P., Morgunova E., … Hughes T.R., Lemaire P., Ukkonen E., Kivioja T., Taipale J. DNA-binding specificities of human transcription factors. Cell. 2013;152(1-2):327-339. doi 10.1016/j.cell.2012.12.009Jolma A., Yin Y., Nitta K.R., Dave K., Popov A., Taipale M., Enge M., Kivioja T., Morgunova E., Taipale J. DNA-dependent formation of transcription factor pairs alters their binding specificity. Nature. 2015;527(7578):384-388. doi 10.1038/nature15518Jolma A., Yin Y., Nitta K.R., Dave K., Popov A., Taipale M., Enge M., Kivioja T., Morgunova E., Taipale J. DNA-dependent formation of transcription factor pairs alters their binding specificity. Nature. 2015;527(7578):384-388. doi 10.1038/nature15518Khan S.F., Damerell V., Omar R., Du Toit M., Khan M., Maranyane H.M., Mlaza M., Bleloch J., Bellis C., Sahm B.D.B., Peres J., ArulJothi K.N., Prince S. The roles and regulation of TBX3 in development and disease. Gene. 2020;726:144223. doi 10.1016/j.gene. 2019.144223Khan S.F., Damerell V., Omar R., Du Toit M., Khan M., Maranyane H.M., Mlaza M., Bleloch J., Bellis C., Sahm B.D.B., Peres J., ArulJothi K.N., Prince S. The roles and regulation of TBX3 in development and disease. Gene. 2020;726:144223. doi 10.1016/j.gene. 2019.144223Lambert M., Jambon S., Depauw S., David-Cordonnier M.-H. Targeting transcription factors for cancer treatment. Molecules. 2018; 23(6):1479. doi 10.3390/molecules23061479Lambert M., Jambon S., Depauw S., David-Cordonnier M.-H. Targeting transcription factors for cancer treatment. Molecules. 2018; 23(6):1479. doi 10.3390/molecules23061479Lang S.H., Smith J., Hyde C., Macintosh C., Stower M., Maitland N.J. Differentiation of prostate epithelial cell cultures by materigel/stromal cell glandular reconstruction. In Vitro Cell Dev Biol Anim. 2006;42(8):273-280. doi 10.1290/0511080.1Lang S.H., Smith J., Hyde C., Macintosh C., Stower M., Maitland N.J. Differentiation of prostate epithelial cell cultures by materigel/stromal cell glandular reconstruction. In Vitro Cell Dev Biol Anim. 2006;42(8):273-280. doi 10.1290/0511080.1Li Y., Song J., Zhou P., Zhou J., Xie S. Targeting undruggable transcription factors with PROTACs: advances and perspectives. J Med Chem. 2022;65(15):10183-10194. doi 10.1021/acs.jmedchem.2c00691Li Y., Song J., Zhou P., Zhou J., Xie S. Targeting undruggable transcription factors with PROTACs: advances and perspectives. J Med Chem. 2022;65(15):10183-10194. doi 10.1021/acs.jmedchem.2c00691Lingbeek M.E., Jacobs J.J.L., van Lohuizen M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem. 2002; 277(29):26120-26127. doi 10.1074/jbc.M200403200Lingbeek M.E., Jacobs J.J.L., van Lohuizen M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem. 2002; 277(29):26120-26127. doi 10.1074/jbc.M200403200Ortiz-Lombardia M., Foos N., Maurel-Zaffran C., Saurin A.J., Graba Y. Hox functional diversity: novel insights from flexible motif folding and plastic protein interaction. BioEssays. 2017;39(4):1600246. doi 10.1002/bies.201600246Ortiz-Lombardia M., Foos N., Maurel-Zaffran C., Saurin A.J., Graba Y. Hox functional diversity: novel insights from flexible motif folding and plastic protein interaction. BioEssays. 2017;39(4):1600246. doi 10.1002/bies.201600246Pomerantz M.M., Qiu X., Zhu Y., Takeda D.Y., Pan W., Baca S.C., Gusev A., … Lee G.-S.M., Corey E., Long H.W., Zwart W., Freedman M.L. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat Genet. 2020;52(8): 790-799. doi 10.1038/s41588-020-0664-8Pomerantz M.M., Qiu X., Zhu Y., Takeda D.Y., Pan W., Baca S.C., Gusev A., … Lee G.-S.M., Corey E., Long H.W., Zwart W., Freedman M.L. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat Genet. 2020;52(8): 790-799. doi 10.1038/s41588-020-0664-8Schuettengruber B., Bourbon H.-M., Di Croce L., Cavalli G. Genome regulation by Polycomb and Trithorax: 70 years and counting. Cell. 2017;171(1):34-57. doi 10.1016/j.cell.2017.08.002Schuettengruber B., Bourbon H.-M., Di Croce L., Cavalli G. Genome regulation by Polycomb and Trithorax: 70 years and counting. Cell. 2017;171(1):34-57. doi 10.1016/j.cell.2017.08.002Siegel R.L., Miller K.D., Wagle N.S., Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48. doi 10.3322/caac.21763Siegel R.L., Miller K.D., Wagle N.S., Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48. doi 10.3322/caac.21763Tsherniak A., Vazquez F., Montgomery P.G., Weir B.A., Kryukov G., Cowley G.S., Gill S., … Garraway L.A., Root D.E., Golub T.R., Boehm J.S., Hahn W.C. Defining a cancer dependency map. Cell. 2017;170(3):564-576.e16. doi 10.1016/j.cell.2017.06.010Tsherniak A., Vazquez F., Montgomery P.G., Weir B.A., Kryukov G., Cowley G.S., Gill S., … Garraway L.A., Root D.E., Golub T.R., Boehm J.S., Hahn W.C. Defining a cancer dependency map. Cell. 2017;170(3):564-576.e16. doi 10.1016/j.cell.2017.06.010Vazquez F., Sellers W.R. Are CRISPR screens providing the next generation of therapeutic targets? Cancer Res. 2021;81(23):5806- 5809. doi 10.1158/0008-5472.CAN-21-1784Vazquez F., Sellers W.R. Are CRISPR screens providing the next generation of therapeutic targets? Cancer Res. 2021;81(23):5806- 5809. doi 10.1158/0008-5472.CAN-21-1784Vishnoi K., Viswakarma N., Rana A., Rana B. Transcription factors in cancer development and therapy. Cancers (Basel). 2020;12(8): 2296. doi 10.3390/cancers12082296Vishnoi K., Viswakarma N., Rana A., Rana B. Transcription factors in cancer development and therapy. Cancers (Basel). 2020;12(8): 2296. doi 10.3390/cancers12082296Webber M.M., Quader S.T.A., Kleinman H.K., Bello‐DeOcampo D., Storto P.D., Bice G., DeMendonca‐Calaca W., Williams D.E. Human cell lines as an in vitro/in vivo model for prostate carcinogenesis and progression. Prostate. 2001;47(1):1-13. doi 10.1002/pros.1041Webber M.M., Quader S.T.A., Kleinman H.K., Bello‐DeOcampo D., Storto P.D., Bice G., DeMendonca‐Calaca W., Williams D.E. Human cell lines as an in vitro/in vivo model for prostate carcinogenesis and progression. Prostate. 2001;47(1):1-13. doi 10.1002/pros.1041Weiner A.B., Faisal F.A., Davicioni E., Karnes R.J., Griend D.J.V., Lotan T.L., Schaeffer E.M. Somatic HOXB13 expression correlates with metastatic progression in men with localized prostate cancer following radical prostatectomy. Eur Urol Oncol. 2021;4(6):955- 962. doi 10.1016/j.euo.2020.05.001Weiner A.B., Faisal F.A., Davicioni E., Karnes R.J., Griend D.J.V., Lotan T.L., Schaeffer E.M. Somatic HOXB13 expression correlates with metastatic progression in men with localized prostate cancer following radical prostatectomy. Eur Urol Oncol. 2021;4(6):955- 962. doi 10.1016/j.euo.2020.05.001Xie X., Yu T., Li X., Zhang N., Foster L.J., Peng C., Huang W., He G. Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials. Signal Transduct Target Ther. 2023;8(1): 335. doi 10.1038/s41392-023-01589-zXie X., Yu T., Li X., Zhang N., Foster L.J., Peng C., Huang W., He G. Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials. Signal Transduct Target Ther. 2023;8(1): 335. doi 10.1038/s41392-023-01589-zYao J., Chen Y., Nguyen D.T., Thompson Z.J., Eroshkin A.M., Nerlakanti N., Patel A.K., … Coppola D., Zhang J., Perera R., Kim Y., Mahajan K. The homeobox gene, HOXB13, regulates a mitotic protein-kinase interaction network in metastatic prostate cancers. Sci Rep. 2019;9(1):9715. doi 10.1038/s41598-019-46064-4Yao J., Chen Y., Nguyen D.T., Thompson Z.J., Eroshkin A.M., Nerlakanti N., Patel A.K., … Coppola D., Zhang J., Perera R., Kim Y., Mahajan K. The homeobox gene, HOXB13, regulates a mitotic protein-kinase interaction network in metastatic prostate cancers. Sci Rep. 2019;9(1):9715. doi 10.1038/s41598-019-46064-4Yarosh W., Barrientos T., Esmailpour T., Lin L., Carpenter P.M., Osann K., Anton-Culver H., Huang T. TBX3 is overexpressed in breast cancer and represses p14ARF by interacting with histone deacetylases. Cancer Res. 2008;68(3):693-699. doi 10.1158/0008-5472.CAN-07-5012Yarosh W., Barrientos T., Esmailpour T., Lin L., Carpenter P.M., Osann K., Anton-Culver H., Huang T. TBX3 is overexpressed in breast cancer and represses p14ARF by interacting with histone deacetylases. Cancer Res. 2008;68(3):693-699. doi 10.1158/0008-5472.CAN-07-5012Yu M., Mazor T., Huang H., Huang H.-T., Kathrein K.L., Woo A.J., Chouinard C.R., … Roeder R.G., Kim C.F., Zon L.I., Fraenkel E., Cantor A.B. Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Mol Cell. 2012; 45(3):330-343. doi 10.1016/j.molcel.2011.11.032Yu M., Mazor T., Huang H., Huang H.-T., Kathrein K.L., Woo A.J., Chouinard C.R., … Roeder R.G., Kim C.F., Zon L.I., Fraenkel E., Cantor A.B. Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Mol Cell. 2012; 45(3):330-343. doi 10.1016/j.molcel.2011.11.032Zabalza C.V., Adam M., Burdelski C., Wilczak W., Wittmer C., Kraft S., Krech T., … Minner S., Simon R., Sauter G., Schlomm T., Tsourlakis M.C. HOXB13 overexpression is an independent predictor of early PSA recurrence in prostate cancer treated by radical prostatectomy. Oncotarget. 2015;6(14):12822-12834. doi 10.18632/oncotarget.3431Zabalza C.V., Adam M., Burdelski C., Wilczak W., Wittmer C., Kraft S., Krech T., … Minner S., Simon R., Sauter G., Schlomm T., Tsourlakis M.C. HOXB13 overexpression is an independent predictor of early PSA recurrence in prostate cancer treated by radical prostatectomy. Oncotarget. 2015;6(14):12822-12834. doi 10.18632/oncotarget.3431Zhang J., Lee D., Dhiman V., Jiang P., Xu J., McGillivray P., Yang H., … Cheng C., Yue F., Liu X.S., White K.P., Gerstein M. An integrative ENCODE resource for cancer genomics. Nat Commun. 2020;11(1):3696. doi 10.1038/s41467-020-14743-wZhang J., Lee D., Dhiman V., Jiang P., Xu J., McGillivray P., Yang H., … Cheng C., Yue F., Liu X.S., White K.P., Gerstein M. An integrative ENCODE resource for cancer genomics. Nat Commun. 2020;11(1):3696. doi 10.1038/s41467-020-14743-wZhuang J.-J., Liu Q., Wu D.-L., Tie L. Current strategies and progress for targeting the “undruggable” transcription factors. Acta Pharmacol Sin. 2022;43(10):2474-2481. doi 10.1038/s41401-021-00852-9Zhuang J.-J., Liu Q., Wu D.-L., Tie L. Current strategies and progress for targeting the “undruggable” transcription factors. Acta Pharmacol Sin. 2022;43(10):2474-2481. doi 10.1038/s41401-021-00852-9

The authors declare that there are no conflicts of interest present.