Abstract
LATS2, a pivotal Ser/Thr kinase of the Hippo pathway, plays important roles in many biological processes. LATS2 also function in Hippo-independent pathway, including mitosis, DNA damage response and epithelial to mesenchymal transition. However, the physiological relevance and molecular basis of these LATS2 functions remain obscure. To understand novel functions of LATS2, we constructed a LATS2 knockout HeLa-S3 cell line using TAL-effector nuclease (TALEN). Integrated omics profiling of this cell line revealed that LATS2 knockout caused genome-wide downregulation of Polycomb repressive complex 2 (PRC2) and H3K27me3. Cell-cycle analysis revealed that downregulation of PRC2 was not due to cell cycle aberrations caused by LATS2 knockout. Not LATS1, a homolog of LATS2, but LATS2 bound PRC2 on chromatin and phosphorylated it. LATS2 positively regulates histone methyltransferase activity of PRC2 and their expression at both the mRNA and protein levels. Our findings reveal a novel signal upstream of PRC2, and provide insight into the crucial role of LATS2 in coordinating the epigenome through regulation of PRC2.
Highlights
Large tumor suppressor 2 (LATS2), a pivotal Ser/Thr kinase of the Hippo signaling pathway, plays important roles in many biological processes, including normal development and tumorigenesis [1]
To explore the cellular functions and/or signals that potentially fluctuate in LATS2 dependent fashion, we established LATS2 knockout (KO) HeLa-S3 strains by inducing TALeffector nuclease (TALEN)-mediated double-strand breaks, followed by successive generation of frameshift mutations by nonhomologous end joining [24]
Expression analysis of CTGF (1.6-fold increase upon LATS2 KO), a downstream target gene of the Hippo pathway that should negatively correlate with LATS2 kinase activity, confirmed downregulation of intrinsic LATS2 expression (Fig 1C)
Summary
Large tumor suppressor 2 (LATS2), a pivotal Ser/Thr kinase of the Hippo signaling pathway, plays important roles in many biological processes, including normal development and tumorigenesis [1]. In canonical Hippo signaling, LATS2 and its homolog LATS1 phosphorylate YAP1 and WWTR1 ( known as YAP and TAZ, respectively), transcription coactivators involved in cell proliferation. Phosphorylation inhibits the function of these proteins by promoting their cytoplasmic retention and degradation, thereby governing contact inhibition, and dysregulation of this process is related to tumor progression. LATS2 functions as a hub for many other tumor-suppressive signaling pathways, such as the tetraploidy checkpoint [2], G1/S checkpoint [3], and DNA-damage response [4,5,6]. PLOS ONE | DOI:10.1371/journal.pone.0158562 July 19, 2016
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