Abstract
BackgroundHuman 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.ResultsIn 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.ConclusionsOur 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.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL)
Expression of HTLV-1 provirus is transcriptionally mediated through the viral transactivator Tax, which potently stimulates the activity of long terminal repeats (LTR) by activating the cellular transcription factor CREB and coactivators such as CREB-binding protein (CBP) and CREB-regulating transcriptional coactivators (CRTCs), known as transducers of regulated CREB activity (TORCs) [4,5,6,7,8,9]
It will be of interest to see whether LKB1 is another repressor of HTLV-1 replication like p53 and p30II, which play a role in viral persistence and transformation [22,23]
Summary
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. ATL is a highly aggressive and fatal malignancy of CD4+ T lymphocytes that develops in 2-5% of carriers, usually after more than 20 years of HTLV-1 latency [1,2]. It is a slow and multifactorial process, progression of ATL tightly correlates with high HTLV-1 proviral load [3]. We have previously characterized the essential roles of Tax, CREB and CRTCs in this process [7,10,11]. We have demonstrated the requirement of CRTCs in Tax activation of the LTR [7]
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