Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through differentially regulating tumor suppressor p53 activity.

Kacie A Gardella,Krishnakali Sarkar,Gloria Fang,Israel Muro,Omayra Mendez,Casey W Wright

doi:10.18632/oncotarget.7539

Kacie A Gardella, Krishnakali Sarkar + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.7539

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Journal: Oncotarget	Publication Date: Feb 20, 2016
Citations: 22	License type: cc-by

Affiliation: The University of Texas at Austin

Abstract

The aryl hydrocarbon receptor nuclear translocator (ARNT) is involved in xenobiotic and hypoxic responses, and we previously showed that ARNT also regulates nuclear factor-κB (NF-κB) signaling by altering the DNA binding activity of the RelB subunit. However, our initial study of ARNT-mediated RelB modulation was based on simultaneous suppression of the two ARNT isoforms, isoform 1 and 3, and precluded the examination of their individual functions. We find here that while normal lymphocytes harbor equal levels of isoform 1 and 3, lymphoid malignancies exhibit a shift to higher levels of ARNT isoform 1. These elevated levels of ARNT isoform 1 are critical to the proliferation of these cancerous cells, as suppression of isoform 1 in a human multiple myeloma (MM) cell line, and an anaplastic large cell lymphoma (ALCL) cell line, triggered S-phase cell cycle arrest, spontaneous apoptosis, and sensitized cells to doxorubicin treatment. Furthermore, co-suppression of RelB or p53 with ARNT isoform 1 prevented cell cycle arrest and blocked doxorubicin induced apoptosis. Together our findings reveal that certain blood cancers rely on ARNT isoform 1 to potentiate proliferation by antagonizing RelB and p53-dependent cell cycle arrest and apoptosis. Significantly, our results identify ARNT isoform 1 as a potential target for anticancer therapies.

Highlights

Hematological malignancies, like many other cancers, often manifest genetic amplification events that alter gene expression and allow unrestrained survival and proliferation [1]
aryl hydrocarbon receptor nuclear translocator (ARNT) amplification is prevalent in human MM cell lines (HMCL) and anaplastic large cell lymphoma (ALCL) cell lines
Examination of various HMCLs by array comparative genomic hybridization displayed frequent focal amplifications of chromosome 1q21 leading to multiple copies of the ARNT locus (Figures 1A and S1A)

Summary

Introduction

Hematological malignancies, like many other cancers, often manifest genetic amplification events that alter gene expression and allow unrestrained survival and proliferation [1]. ARNT is a gene contained within the amplified region of chromosome 1q (1q21.3) and, in MM patients, high levels of ARNT expression are associated with an unfavorable outcome [7]. Based on these observations, in this report we examined whether ARNT regulated the proliferation and survival of malignant blood cells. Deregulation of AHR and HIF1α activity can promote various disease states including cancer proliferation, and ARNT has been shown to be essential in supporting these pathophysiological characteristics [11,12,13,14,15]

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