Evidence for an oncogenic modifier role for mutant histone acetyltransferases in diffuse large B-cell lymphoma

Haery, Leila; Mussakhan, Sultan; Waxman, David J.; Gilmore, Thomas D.

doi:10.3109/10428194.2016.1160083

Cited by 3 publications

(4 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This sensitivity difference might be due to different p53 regulation statuses in positions downstream of CK1α that negative regulator(s) other than MDM2 might act on. For example, C-terminally truncated histone acetyltransferase p300 (p300deltaC) is reportedly expressed in RC-K8 cells ( 48 ), while wild-type p300 is expressed in OCI-Ly3 ( 49 ). Given that p300deltaC knockdown upregulates p53 expression by 2.4-fold ( 48 ), p300deltaC intrinsically suppresses p53 expression in RC-K8 cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, C-terminally truncated histone acetyltransferase p300 (p300deltaC) is reportedly expressed in RC-K8 cells ( 48 ), while wild-type p300 is expressed in OCI-Ly3 ( 49 ). Given that p300deltaC knockdown upregulates p53 expression by 2.4-fold ( 48 ), p300deltaC intrinsically suppresses p53 expression in RC-K8 cells. This might partially account for why CK1α degradation had no effect on p21 expression and cell growth in RC-K8 cells.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling

Kanaoka,

Yamada,

Yokoyama

et al. 2024

Cancer Research Communications

View full text Add to dashboard Cite

Reducing casein kinase 1α (CK1α) expression inhibits the growth of multiple cancer cell lines, making it a potential therapeutic target for cancer. Herein, we evaluated the anti-tumor activity of FPFT-2216—a novel low molecular weight compound—in lymphoid tumors and elucidated its molecular mechanism of action. Additionally, we determined whether targeting CK1α with FPFT-2216 is useful for treating hematopoietic malignancies. FPFT-2216 strongly degraded CK1α and IKAROS family zinc finger 1/3 (IKZF1/3) via proteasomal degradation. FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2. Combining FPFT-2216 with an MDM2 inhibitor exhibited synergistic anti-proliferative activity and induced rapid tumor regression in immuno-deficient mice subcutaneously transplanted with a human lymphoma cell line. Nearly all tumors in mice disappeared after ten days; this was continuously observed in 5/7 mice up to 24 days after the final FPFT-2216 administration. FPFT-2216 also enhanced the anti-tumor activity of rituximab and showed anti-tumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model. Furthermore, FPFT-2216 decreased the activity of the CARD11/BCL10/MALT1 (CBM) complex and inhibited IκBα and NF-κB phosphorylation. These effects were mediated through CK1α degradation and were stronger than those of known IKZF1/3 degraders. In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NF-κB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling

Kanaoka,

Yamada,

Yokoyama

et al. 2024

Cancer Research Communications

View full text Add to dashboard Cite

show abstract

“…Histone modifications, including phosphorylation, methylation, acetylation and ribosylation, represent important epigenetic mechanisms that serve an important role in the regulation of gene expression (20). acetylation by histone acetyltransferase promotes gene expression and Hdac gene expression can lead to silencing of tumor suppressor genes (21). As a key enzyme regulating gene expression, HDAC has an important role in the occurrence and development of hematological malignancies via the promotion of cell proliferation and inhibition of cell apoptosis (22).…”

Section: Discussionmentioning

confidence: 99%

Chidamide induces necroptosis via regulation of c‑FLIPL expression in Jurkat and HUT‑78 cells

et al. 2019

View full text Add to dashboard Cite

T-cell acute lymphoblastic leukemia (T-all) is a hematopoietic malignancy, which is associated with a poor prognosis. It is difficult to achieve complete remission or long-term survival with conventional chemotherapy, partly due to decreased apoptosis. However, necroptosis can serve as an alternative pathway to induce cell death. The present study investigated whether the selective histone deacetylase (Hdac) inhibitor chidamide exerted a therapeutic effect on T-all and explored the underlying mechanism. The results revealed that HDAC expression was increased in Jurkat and HuT-78 cells treated compared with the control cell line (H9), and was accompanied by elevated cellular Fas-associated death domain-like interleukin-1β converting enzyme inhibitory protein long form (c-FLIP l ) levels. Chidamide treatment (2 µmol/l) also induced mitochondrial dysfunction, necroptosis and apoptosis in T-all cells in vitro. Furthermore, necroptosis was increased when apoptosis was blocked in T-all cells. additionally, chidamide (2 µmol/l) downregulated c-FliP l , Hdac1 and Hdac3 expression, and increased receptor-interacting protein kinase 3 expression and the phosphorylation of mixed lineage kinase domain-like pseudokinase in Jurkat and HuT-78 cells. The results obtained in the present study revealed that chidamide may induce necroptosis via regulation of c-FliP l expression when apoptosis is inhibited in Jurkat and HuT-78 cells.

show abstract

“…CBP/p300 bromodomain inhibition blocks GATA1 and MYC oncogene expression and induces chronic myeloid leukemia and lymphoma cell cycle arrest and growth inhibition 72 . In diffuse large B-cell lymphoma cells with C-terminal truncated HAT domain-deficient p300, the truncated p300 suppresses NF-κB and REL activity, reduces p53 expression, and is required for lymphoma cell proliferation 37 , 73 (Table 1 ).…”

Section: Cbp/p300 Induce Oncogene Transcription Cancer Cell Prolifera...mentioning

confidence: 99%

Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents

Chen¹,

Yang²,

Liu³

et al. 2022

Theranostics

View full text Add to dashboard Cite

The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo . In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.

show abstract

Evidence for an oncogenic modifier role for mutant histone acetyltransferases in diffuse large B-cell lymphoma

Cited by 3 publications

References 42 publications

FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling

FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling

Chidamide induces necroptosis via regulation of c‑FLIPL expression in Jurkat and HUT‑78 cells

Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents

Contact Info

Product

Resources

About