TY - JOUR
T1 - UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma
AU - Reardon, Emily S.
AU - Shukla, Vivek
AU - Xi, Sichuan
AU - Gara, Sudheer K.
AU - Liu, Yi
AU - Straughan, David
AU - Zhang, Mary
AU - Hong, Julie A.
AU - Payabyab, Eden C.
AU - Kumari, Anju
AU - Richards, William G.
AU - De Rienzo, Assunta
AU - Hassan, Raffit
AU - Miettinen, Markku
AU - Xi, Liqiang
AU - Raffeld, Mark
AU - Uechi, Lisa T.
AU - Li, Xinmin
AU - Wang, Ruihong
AU - Chen, Haobin
AU - Hoang, Chuong D.
AU - Bueno, Raphael
AU - Schrump, David S.
N1 - Publisher Copyright:
© 2020 International Association for the Study of Lung Cancer
PY - 2021/1
Y1 - 2021/1
N2 - Introduction: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. Methods: Microarray, real-time quantitative reverse transcription–polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. Results: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. Conclusions: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.
AB - Introduction: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. Methods: Microarray, real-time quantitative reverse transcription–polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. Results: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. Conclusions: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.
KW - DNMT1
KW - Epigenetics
KW - Malignant pleural mesothelioma
KW - Prognosis
KW - Therapeutic target
KW - UHRF1
UR - http://www.scopus.com/inward/record.url?scp=85092220915&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2020.08.024
DO - 10.1016/j.jtho.2020.08.024
M3 - Article
C2 - 32927122
AN - SCOPUS:85092220915
SN - 1556-0864
VL - 16
SP - 89
EP - 103
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 1
ER -