Hsp105β upregulates <i>hsp70</i> gene expression through signal transducer and activator of transcription‐3

Yamagishi, Nobuyuki; Fujii, Hajime; Saito, Youhei; Hatayama, Takumi

doi:10.1111/j.1742-4658.2009.07311.x

Cited by 27 publications

(27 citation statements)

References 33 publications

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“…Involvement of HSPH1 nuclear b isoform 24 in TF activation 17 indicates that it may similarly favor Bcl-6 and c-Myc activity by stabilizing their expression on their target genes, as was already described for HSP90 and Bcl-6. The lack of effective strategy to directly inhibit either Bcl-6 or c-Myc further highlights the significance of our findings.…”

Section: Resultssupporting

confidence: 53%

“…HSPH1 knockdown was consistently associated with the downregulation of c-Myc and Bcl-6 ( Figure 1A). Further characterization of 2 HSPH1-silenced (siHSPH1_1 and siHSPH1_2) Namalwa cultures vs the MOCK counterpart revealed a significant proliferation delay and increased doubling time (supplemental Figure 1A), but not enhanced cell death (not shown) nor any reduction in expression or activation status of the previously reported HSPH1 client proteins STAT3 14 and p53, 15,16 or other HSP-familyrelated members 17 (supplemental Figure 1B). This supported the specific relationship between downregulation of HSPH1, c-Myc, Bcl-6, and antilymphoma effects.…”

Section: Resultsmentioning

confidence: 76%

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HSPH1 inhibition downregulates Bcl-6 and c-Myc and hampers the growth of human aggressive B-cell non-Hodgkin lymphoma

Zappasodi

Ruggiero

Guarnotta

et al. 2015

Blood

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Key Points• In human aggressive B-NHLs, HSPH1 favors c-Myc and Bcl-6 expression, and its inhibition provides significant antilymphoma activity.• HSPH1 is expressed in function of Bcl-6 and c-Myc and constitutes a valuable alternative lymphoma therapeutic target of aggressive B-NHLs.We have shown that human B-cell non-Hodgkin lymphomas (B-NHLs) express heat shock protein (HSP)H1/105 in function of their aggressiveness. Here, we now clarify its role as a functional B-NHL target by testing the hypothesis that it promotes the stabilization of key lymphoma oncoproteins. HSPH1 silencing in 4 models of aggressive B-NHLs was paralleled by Bcl-6 and c-Myc downregulation. In vitro and in vivo analysis of HSPH1-silenced Namalwa cells showed that this effect was associated with a significant growth delay and the loss of tumorigenicity when 10 4 cells were injected into mice. Interestingly, we found that HSPH1 physically interacts with c-Myc and Bcl-6 in both Namalwa cells and primary aggressive B-NHLs. Accordingly, expression of HSPH1 and either c-Myc or Bcl-6 positively correlated in these diseases. Our study indicates that HSPH1 concurrently favors the expression of 2 key lymphoma oncoproteins, thus confirming its candidacy as a valuable therapeutic target of aggressive B-NHLs. (Blood. 2015;125(11):1768-1771 IntroductionWe have recently demonstrated that heat shock protein (HSP)H1/ 105 is a novel antigen and potential therapeutic target of B-cell nonHodgkin lymphomas (B-NHLs). We showed that it is expressed in function of B-NHL aggressiveness, and its targeting by a specific antibody (Ab) provides significant therapeutic activity against human aggressive B-NHLs in vivo. 1 We have now set out to clarify its role as a potential molecular target in these diseases.High-grade B-NHLs-including diffuse large B-cell lymphoma (DLBCL) with its numerous subtypes, and Burkitt lymphoma (BL)-account for ;60% of NHL cases.2 Despite their high response rate to anti-CD20 rituximab-based chemoimmunotherapy, alternative strategies are required to manage relapse and resistance, which still pose a very high risk of death in approximately one-third of cases.3 Sustained expression of Bcl-6 or c-Myc oncoprotein is the best-recognized trait of DLBCL 4 or BL, 5 respectively, whereas their concurrent overexpression defines a subset of aggressive B-NHLs with an extremely unfavorable prognosis.6 Although these transcription factors (TFs) have long been regarded as reliable lymphoma targets, 7,8 their selective inhibition has proven challenging. To ensure constitutive high expression of key oncoproteins, NHLs have shown to upregulate HSP90 and HSP70, 9,10 which assist protein folding and prevent protein degradation.11 Investigation of HSP90 inhibitors has thus been extended to lymphoma patients. 12Here we provide evidence that HSPH1 constitutes a viable alternative therapeutic target of aggressive B-NHLs insofar as the in vitro and in vivo antilymphoma activity determined by its knockdown is strongly associated with both Bcl-6 and c-Myc downmodulation...

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Section: Resultssupporting

confidence: 53%

Section: Resultsmentioning

confidence: 76%

HSPH1 inhibition downregulates Bcl-6 and c-Myc and hampers the growth of human aggressive B-cell non-Hodgkin lymphoma

Zappasodi

Ruggiero

Guarnotta

et al. 2015

Blood

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“…Regulation of the Hsp70 Promoter by STAT-3 and Elp2-Previous data suggest that STAT-3 may bind to the Hsp70 promoter between Ϫ206 and Ϫ187 bp (37). We tested whether the binding of STAT3 to Hsp70 promoter is affected by 4PBA.…”

Section: Hsp70 Expression Is Transiently Increased By 4pba-othersmentioning

confidence: 99%

4-Phenylbutyrate Stimulates Hsp70 Expression through the Elp2 Component of Elongator and STAT-3 in Cystic Fibrosis Epithelial Cells

Suaud

Miller

Panichelli

et al. 2011

Journal of Biological Chemistry

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“…32,42 In agreement with a recent report demonstrating the ability of HSP90 to stabilize BCL-6 in normal centroblasts during the affinity maturation process, 43 the preferential localization of HSP105 within the GCs of low-grade lymphomas and normal lymph nodes (data not shown) indicates that GC reaction may be governed by a stress response that may itself be involved in the physiopathology of GC-derived B-cell lymphomas. In keeping with this hypothesis, overexpression of the alternative splicing variant HSP105␤ has been found to stimulate the phosphorylation of STAT3, 26,27,44,45 which constitutes a crucial signaling node of B-NHLs. [46][47][48] Increasing evidence is pointing to the stress response pathway as an additional hallmark of cancer and a promising new target for anticancer therapy.…”

Section: Discussionmentioning

confidence: 90%

Serological identification of HSP105 as a novel non-Hodgkin lymphoma therapeutic target

Zappasodi¹,

Bongarzone

Ghedini

et al. 2011

Blood

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IntroductionB-cell non-Hodgkin lymphomas (B-NHLs) are lymphoproliferative malignancies that encompass different biologic and histologic subtypes and arise from mature B cells within secondary lymphoid organs. 1,2 Although these tumors are highly sensitive to both chemotherapy and radiotherapy, 3 the ultimate goal of curing all NHLs remains to be attained. The last 20 years have demonstrated that the chimeric monoclonal antibody (mAb) rituximab has been the most valuable addition to the B-NHL treatment armamentarium. At present, its combination with poly-chemotherapy still represents the standard of choice for the treatment of both indolent and aggressive B-NHL. 4,5 However, given the difficulties in the management of relapse and resistance to rituximab 6,7 and the late toxicities associated with its administration, 8 it seems that treatment of B-NHL may have reached a new plateau. Alternative approaches as well as new molecular targets are thus required to ameliorate management and clinical outcome of the many patients that become resistant to rituximab.We have recently reported that vaccination with autologous dendritic cells (DCs) pulsed with autologous killed tumor cells elicited clinical responses associated with tumor-specific immune activation in 6 of 18 relapsed indolent B-NHL patients. 9 This points to the existence of novel, NHL-restricted therapeutic antigens. Immunohistochemistry (IHC) using patients' circulating immunoglobulins (Igs) on autologous lymphoma biopsies showed that our protocol induced tumor-restricted Ab responses only when it was clinically efficacious. 9 In the present study, we have looked to see whether the antitumor humoral immunity developed in responders was directed against shared NHL-restricted antigen(s). Demonstration of such cross-reactivity constituted the prerequisite for exploitation of the responders' Ab repertoires to discover new lymphoma antigens to be targeted in NHL immunotherapy. We have used an appropriately modified serological proteome-based approach (SERPA) to identify the proteins differentially recognized by these repertoires. HSP105 was one of these proteins. It has been extensively shown that HSP105/110, together with HSP90, HSP70, HSP60, HSP40, and HSP27 classes of proteins, guide the normal folding, intracellular disposition, and proteolytic turnover of many of the key regulators of cell growth, differentiation, and survival, including HER2, mutant HER1, c-KIT, BCR-ABL, Akt, Cdk4, BRAF, HIF1-␣, p53, and other oncoproteins. [10][11][12] Despite the focus on oncogenes as cancer therapy targets, sound experimental evidence demonstrates that targeting stress proteins could also be effective by promoting the destabilization of their client proteins. 10,[13][14][15][16] Our findings show that HSP105 is immunogenic in NHL oncotype and expressed on the plasma membrane and in the For personal use only. on March 28, 2019. by guest www.bloodjournal.org From cytoplasm of human B-NHL cell lines and specimens, with significantly higher intensity in highly proliferating ...

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Hsp105β upregulates hsp70 gene expression through signal transducer and activator of transcription‐3

Cited by 27 publications

References 33 publications

HSPH1 inhibition downregulates Bcl-6 and c-Myc and hampers the growth of human aggressive B-cell non-Hodgkin lymphoma

HSPH1 inhibition downregulates Bcl-6 and c-Myc and hampers the growth of human aggressive B-cell non-Hodgkin lymphoma

4-Phenylbutyrate Stimulates Hsp70 Expression through the Elp2 Component of Elongator and STAT-3 in Cystic Fibrosis Epithelial Cells

Serological identification of HSP105 as a novel non-Hodgkin lymphoma therapeutic target

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