HOXA10 is associated with temozolomide resistance through regulation of the homologous recombinant DNA repair pathway in glioblastoma cell lines

Kim, Jin Wook; Kim, Ji Young; Kim, Ja Eun; Kim, Seung-Ki; Chung, Hyun‐Tai; Park, Shin Young

doi:10.18632/genesandcancer.16

Cited by 29 publications

(14 citation statements)

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“…In the present study we sought to elucidate underlying molecular mechanisms triggering the inappropriate expression of a HOX-signature. Such a HOX gene dominated expression signature has been associated by others, and us with resistance to temozolomide and conferring of glioma-initiating properties [ 7 , 8 , 11 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…The abnormal expression of a HOX gene signature has been confirmed recently in GICs, where it has been functionally associated with their glioma initiating potential [ 8 ]. The importance of HOX gene expression for gliomagenesis and treatment resistance to temozolomide has been emphasized in several studies [ 8 - 12 ]. In 2006, Krivtsov and colleagues first described the inappropriate expression of a HOX gene signature in acute myeloid leukemia (AML) [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma

et al. 2015

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BackgroundHOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma.ResultsWe observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively.ConclusionsBased on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0583-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma

et al. 2015

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“…Since several genes are reportedly involved in TMZ resistance, we investigated whether PLD1 affects the expression of TMZ resistance factors in GSCs. Interestingly, PLD1 depletion, but not TMZ treatment, markedly suppressed the expression of several TMZ resistance factors ( MGMT , ABCB1 , ABCG2 , PHF6 , MMP16 , and MCL1 ), but not HOXA9 and HOXA10 [26–30], in non‐sorted GSC‐X01 (Figure 4A). TMZ treatment and PLD1 depletion further suppressed the expression of the TMZ resistance factors.…”

Section: Resultsmentioning

confidence: 99%

Phospholipase D1 inhibition sensitizes glioblastoma to temozolomide and suppresses its tumorigenicity

Kang

Hwang

Noh

et al. 2020

The Journal of Pathology

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Resistance of glioblastoma to the chemotherapeutic compound temozolomide is associated with the presence of glioblastoma stem cells in glioblastoma and is a key obstacle for the poor prognosis of glioblastoma. Here, we show that phospholipase D1 is elevated in CD44 High glioblastoma stem cells and in glioblastoma, especially recurring glioblastoma. Phospholipase D1 elevation positively correlated with the level of CD44 and poor prognosis in glioblastoma patients. Temozolomide significantly upregulated the expression of phospholipase D1 in the low and moderate CD44 populations of glioblastoma stem cells, but not in the CD44 High population in which phospholipase D1 is highly expressed. Phospholipase D1 conferred resistance to temozolomide in CD44 High glioblastoma stem cells and increased their self-renewal capacity and maintenance. Phospholipase D1 expression significantly correlated with levels of temozolomide resistance factors, which were suppressed by microRNA-320a and-4496 induced by phospholipase D1 inhibition. Genetic and pharmacological targeting of phospholipase D1 attenuated glioblastoma stem cellderived intracranial tumors of glioblastoma using the microRNAs, and improved survival. Treatment solely with temozolomide produced no benefits on the glioblastoma, whereas in combination, phospholipase D1 inhibition sensitized glioblastoma stem cells to temozolomide and reduced glioblastoma tumorigenesis. Together, these findings indicate that phospholipase D1 inhibition might overcome resistance to temozolomide and represents a potential treatment strategy for glioblastoma.

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“…EGR1 is a Cys2-His2-type zinc finger transcription factor that in GB cell lines has been shown to bind to GC-rich sites of the TGF-β promotor leading to decreased proliferation and suppressing transformation [68]. In contrast, another study showed that EGR1 induces U251 cell migration via activation of fibronectin [69]; and other reports indicated that EGR1 confers temozolomide resistance in GB [70,71]. EGR1 has also been shown to promote a glioma stem cell-like phenotype [72,73].…”

Section: Discussionmentioning

confidence: 99%

Investigating Glioblastoma Response to Hypoxia

et al. 2020

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Glioblastoma (GB) is the most common and deadly type of primary malignant brain tumor with an average patient survival of only 15–17 months. GBs typically have hypoxic regions associated with aggressiveness and chemoresistance. Using patient derived GB cells, we characterized how GB responds to hypoxia. We noted a hypoxia-dependent glycolytic switch characterized by the up-regulation of HK2, PFKFB3, PFKFB4, LDHA, PDK1, SLC2A1/GLUT-1, CA9/CAIX, and SLC16A3/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD, PGF/PlGF, ADM, ANGPTL4, and SERPINE1/PAI-1 were up-regulated during hypoxia. We detected the hypoxic induction of invasion proteins, including the plasminogen receptor, S100A10, and the urokinase plasminogen activator receptor, uPAR. Furthermore, we observed a hypoxia-dependent up-regulation of the autophagy genes, BNIP-3 and DDIT4 and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation of EGR1 and TFRC (Graphical abstract). Analysis of GB patient cohorts’ revealed differential expression of these genes in patient samples (except SLC16A3) compared to non-neoplastic brain tissue. High expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, TFRC, and ADM was associated with significantly lower overall survival. Together these data provide important information regarding GB response to hypoxia which could support the development of more effective treatments for GB patients.

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HOXA10 is associated with temozolomide resistance through regulation of the homologous recombinant DNA repair pathway in glioblastoma cell lines

Abstract: ABSTRACT:Temozolomide resistance is associated with multiple DNA repair pathways. We investigated homeobox (HOX) genes for their role in temozolomide resistance

Cited by 29 publications

References 44 publications

Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma

Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma

Phospholipase D1 inhibition sensitizes glioblastoma to temozolomide and suppresses its tumorigenicity

Investigating Glioblastoma Response to Hypoxia

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