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

Abstract

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...

Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cellsin vitroandin vivo

“…As with many proteins in the cell c-MYC associates with chaperones to maintain its tertiary structure and thereby function. Well-recognized chaperones for c-MYC include HSPH1/p105 – a member of the HSP70 superfamily, and HSP60, a chaperone we have previously shown to be inhibited by [pazopanib + sildenafil] [18, 19]. [Pazopanib + sildenafil] treatment reduced c-MYC expression and reduced both HSPH1/p105 and c-MYC co-localization concomitant with reduced the nuclear/peri-nuclear staining of c-MYC (Figures 2B and 2C).…”

Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells

“…HSP chaperone proteins that bind to denatured and unfolded proteins and promote protein refolding or degradation are known to be positively regulated by AMPK (34). Our proteomic and transcriptome analyses highlight the activation of HSP-associated transcription factors MYC and FOXM1, which both cooperate with HSPs to promote tumor progression (43,44), and the upregulation of co-chaperone immunophilin protein FKBP5 that interacts with HSP90. Thus, HSP activation is supporting AMoL cell survival under co-culture conditions.…”

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

“…Therefore, we built a 10 gene signature, BROMO-10, which is able to discriminate patients with poorer outcome, which takes into account chromatin structure and additionally incorporates key PC-specific downstream targets of BRDs. Interestingly these targets include FEN1 , which we have previously described to be important for PC progression and proposed as a tissue biomarker for biochemical recurrence (Urbanucci et al, 2012), EEF1A2 which has been proposed as a marker of prostate cell transformation (Scaggiante et al, 2012; Sun et al, 2014), KAT2A , which encodes a histone acetyl-transferase controlling the PI3/AKT pathway with therapeutic potential in leukemia (Sun et al, 2015), and HSPH1 which enhances MYC transcription and drives B-cell non-Hodgkin lymphoma (Zappasodi et al, 2015). …”