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

Hei Man Vincent Tang, Wei Wei Gao, Ching Ping Chan, Yeung Tung Siu, Chi Ming Wong, Kin Hang Kok, Yick Pang Ching, Hiroshi Takemori, Dong Yan Jin

Research output: Journal article publicationJournal articleAcademic researchpeer-review

19 Citations (Scopus)

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.
Original languageEnglish
Article number40
JournalRetrovirology
Volume10
Issue number1
DOIs
Publication statusPublished - 11 Apr 2013
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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