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Open Access Highly Accessed Research

LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription

Hei-Man Vincent Tang1, Wei-Wei Gao1, Ching-Ping Chan1, Yeung-Tung Siu1, Chi-Ming Wong1, Kin-Hang Kok1, Yick-Pang Ching2, Hiroshi Takemori3 and Dong-Yan Jin1*

Author Affiliations

1 Department of Biochemistry, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong

2 Department of Anatomy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong

3 Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation, Osaka, Japan

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Retrovirology 2013, 10:40  doi:10.1186/1742-4690-10-40

Published: 11 April 2013

Abstract

Background

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Treatment options are limited and prophylactic agents are not available. We have previously demonstrated an essential role for CREB-regulating transcriptional coactivators (CRTCs) in HTLV-1 transcription.

Results

In this study we report on the negative regulatory role of LKB1 tumor suppressor and salt-inducible kinases (SIKs) in the activation of HTLV-1 long terminal repeats (LTR) by the oncoprotein Tax. Activation of LKB1 and SIKs effectively blunted Tax activity in a phosphorylation-dependent manner, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function. Activated LKB1 and SIKs associated with Tax and suppressed Tax-induced LTR activation by counteracting CRTCs and CREB. Enforced expression of LKB1 or SIK1 in cells transfected with HTLV-1 molecular clone pX1MT repressed proviral transcription. On the contrary, depletion of LKB1 in pX1MT-transfected cells and in HTLV-1-transformed T cells boosted the expression of Tax. Treatment of HTLV-1 transformed cells with metformin led to LKB1/SIK1 activation, reduction in Tax expression, and inhibition of cell proliferation.

Conclusions

Our findings revealed a new function of LKB1 and SIKs as negative regulators of HTLV-1 transcription. Pharmaceutical activation of LKB1 and SIKs might be considered as a new strategy in anti-HTLV-1 and anti-ATL therapy.

Keywords:
Adult T-cell leukemia; Human T-cell leukemia virus type 1; LKB1 tumor suppressor; Salt-inducible kinases; Metformin; Tax oncoprotein