Dataset Information

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers.

ABSTRACT: p300 is one of several acetyltransferases that regulate FOXP3 acetylation and functions. Our recent studies have defined a complex set of histone acetyltransferase interactions which can lead to enhanced or repressed changes in FOXP3 function. We have explored the use of a natural p300 inhibitor, Garcinol, as a tool to understand mechanisms by which p300 regulates FOXP3 acetylation. In the presence of Garcinol, p300 appears to become disassociated from the FOXP3 complex and undergoes lysosome-dependent degradation. As a consequence of p300's physical absence, FOXP3 becomes less acetylated and eventually degraded, a process that cannot be rescued by the proteasome inhibitor MG132. p300 plays a complex role in FOXP3 acetylation, as it could also acetylate a subset of four Lys residues that repressively regulate total FOXP3 acetylation. Garcinol acts as a degradation device to reduce the suppressive activity of regulatory T cells (Treg) and to enhance the in vivo anti-tumor activity of a targeted therapeutic anti-p185(her2/neu) (ERBB2) antibody in MMTV-neu transgenics implanted with neu transformed breast tumor cells. Our studies provide the rationale for molecules that disrupt p300 stability to limit Treg functions in targeted therapies for cancers.

SUBMITTER: Du T

PROVIDER: S-EPMC3963828 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers.

Du Taofeng T Nagai Yasuhiro Y Xiao Yan Y Greene Mark I MI Zhang Hongtao H

Experimental and molecular pathology 20130502 1

p300 is one of several acetyltransferases that regulate FOXP3 acetylation and functions. Our recent studies have defined a complex set of histone acetyltransferase interactions which can lead to enhanced or repressed changes in FOXP3 function. We have explored the use of a natural p300 inhibitor, Garcinol, as a tool to understand mechanisms by which p300 regulates FOXP3 acetylation. In the presence of Garcinol, p300 appears to become disassociated from the FOXP3 complex and undergoes lysosome-de ...[more]

PMID: 23644046

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Project description:AbstractIn an earlier publication, a binary classification of chronic diseases has been proposed. Chronic diseases were classified as “high Treg” or “low Treg” diseases depending on whether the pro-inflammatory or the anti-inflammatory arms of the immune response are deficient. The present work uses this model to analyze the interplay between cancer and the immune system, based on published literature. The work leans upon the etiology of alcohol and tobacco-related malignancies. The main conclusions are: triggers of specific “high Treg” immune reaction promote most non-hematologic cancers, whereas triggers of “low Treg” immune reaction promote lymphomas. The opposite is also true: triggers of specific “high Treg” immune reaction suppress lymphoma, whereas triggers of “low Treg” immune reaction suppress non-hematologic cancers. Both lymphoma and autoimmune diseases are “low Treg” conditions. For this reason, both are promoted by the same panel of “low Treg” bacteria and parasites and are inhibited by “high Treg” triggers. For example, alcohol consumption, a “high Treg” trigger, protects against lymphoma and autoimmune hypothyroidism. In addition, the same immune-modulatory drugs are effective in the treatment of both lymphoma and autoimmune diseases. Like other cancers, lymphoma transforms from a “low Treg” type at early stage of the disease into a “high Treg” type at advanced stages. However, lymphoma is distinguished from most other cancers by the length of time it dwells at an indolent “low Treg” state (many years) before lymphoma cells sensitivity to transforming growth factor-beta is impaired. This impairment stimulates the switch from “low Treg” into “high Treg” response and results in immune escape. The application of this analysis to the pharmacological activity of checkpoint inhibitors forecasts that checkpoint inhibitors would not be effective in low-grade, indolent lymphomas. As of now, checkpoint inhibitors are approved for the treatment of advanced lymphoma only.

Dataset Information

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers.

Publications

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers.

Similar Datasets

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