Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma

Kikuchi, Jiro; Wada, Taeko; Shimizu, R; Izumi, Tohru; Akutsu, Miyuki; Mitsunaga, Kanae; Noborio-Hatano, Kaoru; Nobuyoshi, Masaharu; Ozawa, Keiya; Kano, Yasuhiko; Furukawa, Yusuke

doi:10.1182/blood-2009-07-235663

Cited by 121 publications

(142 citation statements)

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“…Indeed, bortezomib treatment has been demonstrated to have effects on gene demethylation. [44][45] In our study, however, gene expression analysis in both newly diagnosed and in relapse patients was performed prior to bortezomib treatment.…”

Section: Discussionmentioning

confidence: 99%

Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy

Duin¹,

Broyl²,

Knegt³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundIn multiple myeloma, expression of cancer testis antigens may provide prognostic markers and potential targets for immunotherapy. Expression at relapse has not yet been evaluated for a large panel of cancer testis antigens which can be classified by varying expression in normal tissue: restricted to testis, expressed in testis and brain and not restricted but selectively expressed in testis. Design and MethodsEvaluation of cancer testis antigen expression was made in newly diagnosed multiple myeloma cases (HOVON-65/GMMG-HD4 trial; n=320) and in relapse cases (APEX, SUMMIT, CREST trials; n=264). Presence of expression using Affymetrix GeneChips was determined for 123 cancer testis antigens. Of these 87 had a frequency of more than 5% in the newly diagnosed and relapsed patients, and were evaluated in detail. ResultsTissue restriction was known for 58 out of 87 cancer testis antigens. A significantly lower frequency of presence calls in the relapsed compared to newly diagnosed cases was found for 3 out of 13 testis restricted genes, 2 out of 7 testis/brain restricted genes, and 17 out of 38 testis selective genes. MAGEC1, MAGEB2 and SSX1 were the most frequent testis-restricted cancer testis antigens in both data sets. Multivariate analysis demonstrated that presence of MAGEA6 and CDCA1 were clearly associated with shorter progression free survival, and presence of MAGEA9 with shorter overall survival in the set of newly diagnosed cases. In the set of relapse cases, presence of CTAG2 was associated with shorter progression free survival and presence of SSX1 with shorter overall survival. ConclusionsRelapsed multiple myeloma reveals extensive cancer testis antigen expression. Cancer testis antigens are confirmed as useful prognostic markers in newly diagnosed multiple myeloma patients and in relapsed multiple myeloma patients.The HOVON-65/GMMG-HD4 trial is registered under Dutch trial register n. respectively.

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Section: Discussionmentioning

confidence: 99%

Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy

Duin¹,

Broyl²,

Knegt³

et al. 2011

Haematologica

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“…Recent literature suggests that HDACs are also implicated in the drug resistance of B-cell malignancies such as multiple myeloma. 18,19 Given the causative role of HDACs in cancer, small molecular inhibitors of HDACs are expected to constitute a novel class of anticancer drugs. HDAC inhibitors are able to restore the expression of genes that are aberrantly repressed in tumor cells, leading to cell-cycle arrest, differentiation and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

et al. 2010

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Anti-CD20 antibody rituximab is now essential for the treatment of CD20-positive B-cell lymphomas. Decreased expression of CD20 is one of the major mechanisms underlying both innate and acquired resistance to rituximab. In this study, we show that histone deacetylase (HDAC) inhibitors augment the cytotoxic activity of rituximab by enhancing the surface expression of CD20 antigen on lymphoma cells. HDAC inhibitors, valproic acid (VPA) and romidepsin, increased CD20 expression at protein and mRNA levels in B-cell lymphoma cell lines with relatively low CD20 expression levels. The VPA-mediated increase in CD20 expression occurred at 1 mM, which is clinically achievable and safe, but insufficient for inducing cell death. Chromatin immunoprecipitation assays revealed that HDAC inhibitors transactivated the CD20 gene through promoter hyperacetylation and Sp1 recruitment. HDAC inhibitors potentiated the activity of rituximab in complementdependent cytotoxic assays. In mouse lymphoma models, HDAC inhibitors enhanced CD20 expression along with histone hyperacetylation in transplanted cells, and acted synergistically with rituximab to retard their growth. The combination with HDAC inhibitors may serve as an effective strategy to overcome rituximab resistance in B-cell lymphomas.

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“…Recently, Kikuchi et al reported that bortezomib inhibits expression of class I histone deacetylases (HDAC) including HDAC1 and HDAC2, that ultimately results in elevated amounts of acetylated histones. 35 Inhibition of HDACs has been shown earlier to induce transcription of multiple genes. 36 Thus, we hypothesized that transcriptional up-regulation of KLF9 by bortezomib occurs at least in part via an HDAC inhibition-dependent mechanism.…”

mentioning

confidence: 99%

KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells

Mannava¹,

Zhuang²,

Nair³

et al. 2012

Blood

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Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators required for bortezomibinduced apoptosis in MM cells are largely unknown. Using gene expression profiling, we identified 36 transcription factors that displayed altered expression in MM cells treated with bortezomib. Analysis of a publically available database identified Kruppel-like family factor 9 (KLF9) as the only transcription factor with significantly higher basal expression in MM cells from patients who responded to bortezomib compared with nonresponders. We demonstrated that KLF9 in cultured MM cells was up-regulated by bortezomib; however, it was not through the induction of endoplasmic reticulum stress. Instead, KLF9 levels correlated with bortezomib-dependent inhibition of histone deacetylases (HDAC) and were increased by the HDAC inhibitor LBH589 (panobinostat). Furthermore, bortezomib induced binding of endogenous KLF9 to the promoter of the proapoptotic gene NOXA. Importantly, KLF9 knockdown impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589, or a combination of theses drugs, whereas KLF9 overexpression induced apoptosis that was partially NOXA-dependent. Our data identify KLF9 as a novel and potentially clinically relevant transcriptional regulator of drug-induced apoptosis in MM cells. (Blood. 2012;119(6):1450-1458) IntroductionMultiple myeloma (MM) is a plasma cell disorder that accounts for approximately 10% of all hematologic malignancies. 1,2 Although the introduction of novel agents in the past decade has increased median overall survival of myeloma patients from 30 months to 45-72 months, the disease still remains incurable. [3][4][5] One of these agents, bortezomib (Velcade, PS-341), significantly increased overall survival in patients with relapsed or refractory multiple myeloma when used as a single agent in comparison to high-dose dexamethasone, one of the standard therapies for this disease. [1][2][3][4][5] Bortezomib acts via inhibition of proteasome-mediated protein degradation, ultimately causing death in cells from many types of malignancies, including MM cells. [3][4][5] Bortezomib apoptosisinducing activity has been attributed in part to the alterations in the expression of several BCL2 family proteins, 6 among which the BH3-only protein NOXA appears to play an important role. [7][8][9] NOXA triggers apoptosis by binding to the prosurvival molecule MCL1, thus preventing it from sequestering proteins BAX, BAK and BIM, which are all critical inducers of apoptosis. [9][10][11][12] It has been reported that bortezomib increases NOXA protein levels by suppressing its proteosomal degradation 8 and by transcriptional activation of its gene. 8,13 Recently, several transcription factors including C-MYC, 13,14 ATF3, 15 ATF4, 15,16 and p53 14 have been shown to functionally participate in bortezomib-induced death in cells ...

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Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma

Cited by 121 publications

References 48 publications

Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy

Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells

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