Investigating the molecular mechanism of ATOH1 repression by LKB1

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Title: Investigating the molecular mechanism of ATOH1 repression by LKB1
Author: G M, Alisha
Contributor: University of Helsinki, Faculty of Medicine
Publisher: Helsingin yliopisto
Date: 2019
Thesis level: master's thesis
Abstract: Liver Kinase B1 (LKB1), also known as STK11, is a well-known tumor suppressor and a metabolic regulator, mutated in Peutz-Jeghers syndrome (PJS) and other sporadic cancers. LKB1 regulates several cellular functions: metabolism, polarity, cytoskeleton organization, differentiation, and proliferation by activating 14 AMPK-related downstream substrates. In a recent study, LKB1 was found to maintain intestinal homeostasis by repressing ATOH1 with the involvement of pyruvate dehydrogenase kinase 4 (PDK4). ATOH1 is a transcription factor and master regulator of secretory lineage in the intestine. It has been reported that ATOH1 is epigenetically regulated in inner hair cells and intestinal epithelium via Polycomb repressive complex 2 (PRC2). However, the repression mechanism of ATOH1 by LKB1 is currently unknown. This study aimed to determine the molecular mechanism of ATOH1 repression by LKB1. In this study, Ls174t, a human colorectal adenocarcinoma cell line, was used to investigate ATOH1 induction by LKB1 signaling from two angles: First, involvement of LKB1 downstream substrates was investigated using shRNA mediated knockdown screen. Interestingly, silencing of either MARK4 or SIK3 alone was found to induce ATOH1 and thus mimic silencing of LKB1 unlike other LKB1 substrates including AMPK kinases. A second angle explored possible epigenetic mechanism in ATOH1 repression pathway, using dichloroacetate (DCA, a PDK4 inhibitor) and GSK126 (a PRC2 inhibitor). DCA treatment resulted in no change on the global levels of histone modifications tested. In addition, GSK126 caused the downregulation of ATOH1 in both control and LKB1 depleted condition. Thus, this study concludes that LKB1 represses ATOH1 through MARK4 and SIK3 and that global changes in the histone modifications investigated are not involved in the mechanism.
Subject: LKB1

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