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TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma


Abstract

Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function (GOF) properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference (RNAi) screen in a Burkitt's lymphoma (BL) cell line model. We identified TRRAP, a constituent of several histone acetyltransferase (HAT) complexes, as a critical positive regulator of both mutp53 and wild-type p53 (wtp53) levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, while TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through CRISPR-Cas9 screening, we identified a 109 amino acid region in the N-terminal HEAT repeat region of TRRAP which was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDACs1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.

Abstract

Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function (GOF) properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference (RNAi) screen in a Burkitt's lymphoma (BL) cell line model. We identified TRRAP, a constituent of several histone acetyltransferase (HAT) complexes, as a critical positive regulator of both mutp53 and wild-type p53 (wtp53) levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, while TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through CRISPR-Cas9 screening, we identified a 109 amino acid region in the N-terminal HEAT repeat region of TRRAP which was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDACs1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Immunology, Cell Biology, Biochemistry, Hematology
Language:English
Date:13 April 2018
Deposited On:25 Apr 2018 15:31
Last Modified:19 Aug 2018 15:34
Publisher:American Society of Hematology
ISSN:0006-4971
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1182/blood-2017-09-806679
PubMed ID:29653964

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