title: BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53.
abstract: The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance.
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Er
authors.initials: E
authors.lastname: Nie
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Weining
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tianfu
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tongle
authors.initials: T
authors.lastname: Zhi
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.|State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zhumei
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.|Chinese Glioma Cooperative Group (CGCG), Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.|Chinese Glioma Cooperative Group (CGCG), Nanjing, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: You
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015254:DNA Modification Methylases / Q000096:biosynthesis / Q000235:genetics; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide