Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells

Gatla, Himavanth R.; Zou, Yue; Uddin, Mohammad M.; Singha, Bipradeb; Bu, Pengli; Vančura, Aleš; Vancurova, Ivana

doi:10.1074/jbc.m116.771014

Cited by 40 publications

(58 citation statements)

References 58 publications

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“…Human ovarian cancer SKOV3 and OVCAR3 cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD). Cells were cultured (5 ϫ 10 5 cells/ml) in 6-well plates in RPMI 1640 medium (Invitrogen) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Invitrogen) and antibiotics at 37°C with 5% CO 2 as described (53). For treatment with IFN␥, human recombinant IFN␥ (285-IF-100; R&D Systems, Minneapolis, MN) was reconstituted in sterile water.…”

Section: Cell Culturementioning

confidence: 99%

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The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells

Zou

Uddin

Padmanabhan

et al. 2018

Journal of Biological Chemistry

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The proto-oncogene Bcl3 induces survival and proliferation in cancer cells; however, its function and regulation in ovarian cancer (OC) remain unknown. Here, we show that expression is increased in human OC tissues. Surprisingly, however, we found that in addition to promoting survival, proliferation, and migration of OC cells, Bcl3 promotes both constitutive and interferon-γ (IFN)-induced expression of the immune checkpoint molecule PD-L1. The Bcl3 expression in OC cells is further increased by IFN, resulting in increased transcription. The mechanism consists of an IFN-induced, Bcl3- and p300-dependent promoter occupancy by Lys-314/315 acetylated p65 NF-κB. Blocking PD-L1 by neutralizing antibody reduces proliferation of OC cells overexpressing Bcl3, suggesting that the pro-proliferative effect of Bcl3 in OC cells is partly mediated by PD-L1. Together, this work identifies PD-L1 as a novel target of Bcl3, and links Bcl3 to IFNγ signaling and PD-L1-mediated immune escape.

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Section: Cell Culturementioning

confidence: 99%

“…WCE were prepared as described previously (48,53). Denatured proteins were separated on 12% denaturing polyacrylamide gels and transferred to nitrocellulose membrane (Hybond C; Amersham Biosciences).…”

Section: Western Blot Analysismentioning

confidence: 99%

The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells

Zou

Uddin

Padmanabhan

et al. 2018

Journal of Biological Chemistry

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“…HDACi and Hsp90i are pleotropic anticancer agents, in contrast to the strong rationale for their utilization in CRPC treatment, both drug classes have failed multiple CRPC trials . Factors contributing to the unsuccessful clinical development include but are not limited to Hsp90i‐stimulated prosurvival/adaptive heat shock response and HDACi‐caused over‐potent inhibition of nuclear HDACs, which leads to dose‐limiting cardiovascular toxicities and tumor‐promoting side effects, for example, inducing EMT and upregulating proinflammatory cytokines . Therefore, less disturbance of nuclear HDACs, minimization of heat shock response and avoiding broad disruption of Hsp90 clients are highly desirable when targeting HDAC and/or Hsp90 for CRPC treatment.…”

Section: Discussionmentioning

confidence: 99%

“…While this highlights a rationale for using HDAC inhibitors (HDACis) in PCa treatment, clinically available HDACis SAHA (vorinostat), romidepsin, and panobinostat only shows modest or inferior outcomes in CRPC trials as single‐agent therapy . Furthermore, over‐potent inhibition of nuclear HDACs (such as isoforms 1‐3) promotes numerous side effects including induction of epithelial‐mesenchymal transition (EMT) and upregulation of proinflammatory cytokines that stimulate tumor growth and aggressiveness . Therefore, selective cytoplasmic actions of HDACis are more desirable for treating CRPC.…”

Section: Introductionmentioning

confidence: 88%

Targeting prostate cancer cells with enzalutamide‐HDAC inhibitor hybrid drug 2‐75

Chen

et al. 2019

The Prostate

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Background The progression of castration‐resistant prostate cancer (CRPC) still relies on the function of androgen receptor (AR), achieved by evolving mechanisms to reactivate AR signaling under hormonal therapy. Histone deacetylase inhibitors (HDACis) disrupt cytoplasmic AR chaperone heat shock protein 90 (Hsp90) via HDAC6 inhibition, leading to AR degradation and growth suppression of prostate cancer (PCa) cells. However, current HDACis are not effective in clinical trials treating CRPC. Methods We designed hybrid molecules containing partial chemical scaffolds of AR antagonist enzalutamide (Enz) and HDACi suberoylanilide hydroxamic acid (SAHA) as new anti‐PCa agents. We previously demonstrated that Enz‐HDACi hybrid drug 2‐75 targets both AR and Hsp90, which inhibits the growth of Enz‐resistant C4‐2 cells. In the current study, we further investigate the molecular and cellular actions of 2‐75 and test its anti‐PCa effects in vivo. Results Compared with Enz, 2‐75 had greater AR antagonistic effects by decreasing the stability, transcriptional activity, and nuclear translocation of intracellular AR. In addition to inhibition of full‐length AR (FL AR), 2‐75 downregulated the AR‐V7 variant in multiple PCa cell lines. Mechanistic studies indicated that the AR affinity of 2‐75 retains the drug in the cytoplasm of AR + PCa cells and further directs 2‐75 to the AR‐associated protein complex, which permits localized effects on AR‐associated Hsp90. Further, unlike pan‐HDACi SAHA, the cytoplasm‐retaining property allows 2‐75 to significantly inhibit cytoplasmic HDAC6 with limited impact on nuclear HDACs. These selective cytoplasmic actions of 2‐75 overcome the unfavorable resistance and toxicity properties associated with classical AR antagonists, HDACis, and Hsp90 inhibitors. Finally, 2‐75 showed greater antitumor activities than Enz in vivo on SQ xenografts derived from LNCaP cells. Conclusions Novel therapeutic strategy using newly designed 2‐75 and related AR antagonist‐HDACi hybrid drugs has great potential for effective treatment of CRPC.

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“…HDAC inhibitors have been known to induce apoptosis in cancer cells, however some studies demonstrate that certain classes of HDAC inhibitors induce angiogenesis by regulating different signaling molecules [53]. Gatla et al reported that HDAC inhibitors enhance the expression level of proinflammatory cytokines IL8 and CXCL8 via the activation of IkB kinase, which resulted in enhanced solid tumor growth [54]. Available studies revealed that HDAC inhibitors increase the prosurvival and proinflammatory cytokines mediated through NFkB signaling in solid tumors [55].…”

Section: Epigenetic Modifiers In Clinical Usementioning

confidence: 99%

Flavonoids and Other Polyphenols Act as Epigenetic Modifiers in Breast Cancer

et al. 2020

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Breast cancer is a common cancer that occurs due to different epigenetic alterations and genetic mutations. Various epidemiological studies have demonstrated an inverse correlation between breast cancer incidence and flavonoid intake. The anti-cancer action of flavonoids, a class of polyphenolic compounds that are present in plants, as secondary metabolites has been a major topic of research for many years. Our review analysis demonstrates that flavonoids exhibit anti-cancer activity against breast cancer occurring in different ethnic populations. Breast cancer subtype and menopausal status are the key factors in inducing the flavonoid’s anti-cancer action in breast cancer. The dose is another key factor, with research showing that approximately 10 mg/day of isoflavones is required to inhibit breast cancer occurrence. In addition, flavonoids also influence the epigenetic machinery in breast cancer, with research demonstrating that epigallocatechin, genistein, and resveratrol all inhibited DNA methyltransferase and altered chromatin modification in breast cancer. These flavonoids can induce the expression of different tumor suppressor genes that may contribute to decreasing breast cancer progression and metastasis. Additional studies are required to confirm the contribution of epigenetic modifications by flavonoids to breast cancer prevention.

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Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells

Cited by 40 publications

References 58 publications

The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells

The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells

Targeting prostate cancer cells with enzalutamide‐HDAC inhibitor hybrid drug 2‐75

Flavonoids and Other Polyphenols Act as Epigenetic Modifiers in Breast Cancer

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