The helicase HAGE prevents interferon-a-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1

Mathieu, M.G., Miles, A.K. ORCID: 0000-0002-5388-938X, Ahmad, M. ORCID: 0000-0002-6074-2001, Buczek, M.E., Pockley, A.G. ORCID: 0000-0001-9593-6431, Rees, R.C. ORCID: 0000-0002-4574-4746 and Regad, T. ORCID: 0000-0003-4028-6368, 2014. The helicase HAGE prevents interferon-a-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1. Cell Death and Disease, 5 (2). ISSN 2041-4889

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Abstract

The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5 + malignant melanoma-initiating cells (ABCB5 + MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK-STAT (janus kinase-signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK-STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro.

Item Type:	Journal article
Publication Title:	Cell Death and Disease
Creators:	Mathieu, M.G., Miles, A.K., Ahmad, M., Buczek, M.E., Pockley, A.G., Rees, R.C. and Regad, T.
Publisher:	Nature Publishing Group
Date:	2014
Volume:	5
Number:	2
ISSN:	2041-4889
Identifiers:	Number Type 10.1038/cddis.2014.29 DOI
Rights:	© 2014 Associazione Differenziamento e Morte Cellulare
Divisions:	Schools > School of Science and Technology
Record created by:	EPrints Services
Date Added:	09 Oct 2015 10:39
Last Modified:	11 Oct 2021 13:35
URI:	https://irep.ntu.ac.uk/id/eprint/16106

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