Homozygous deletion of the STK11/LKB1 locus and the generation of novel fusion transcripts in cervical cancer cells

Abstract

The STK11/LKB1 gene encodes a ubiquitously expressed serine/threonine kinase that is mutated in multiple sporadic cancers including non-small cell lung carcinomas, pancreatic cancers, and melanomas. LKB1 affects multiple cellular functions including cell growth, cell cycle progression, metabolism, cell polarity and migration. To date, only a limited number of studies have assessed the status of LKB1 in cervical cancers. Herein, we investigate DNA methylation, DNA mutation, and transcription at the LKB1 locus in cervical cancer cell lines. We identified homozygous deletions of 25-85kb in the HeLa and SiHa cell lines. Deletion breakpoint analysis in HeLa cells revealed that the deletion resulted from an Alu-recombination mediated deletion (ARMD) and generated a novel LKB1 fusion transcript driven by an uncharacterized CpG island promoter located ~11kb upstream of LKB1. Although the homozygous deletion in SiHa cells removes the entire LKB1 gene and portions of the neighboring genes SBNO2 and c19orf26, this deletion also generates a fusion transcript driven by the c19orf26 promoter and comprised of both c19orf26 and SBNO2 sequences. Further analyses of public gene expression and mutation databases suggest that LKB1 and its neighboring genes are frequently dysregulated in primary cervical cancers. Thus, homozygous deletions affecting LKB1 in cervical cancers may generate multiple fusion transcripts involving LKB1, SBNO2, and c19orf26.

AMPK Regulates Mitotic Spindle Orientation through Phosphorylation of Myosin Regulatory Light Chain

“…Both LKB1 (11,30,47) and CamKK (46) activate AMPK by phosphorylation at AMPK thr172 . We propose that the AMPK-MRLC pathway is regulated by CamKK in LKB-deficient cells (e.g., HeLa cells in which LKB1 is homozygously deleted [19]), since inhibition of CamKK caused spindle misorientation, reduced pAMPK thr172 at the spindle poles, and reduced pMRLC ser19 at the spindle poles (Fig. 9).…”

LKB1/AMPK pathway mediates resistin-induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes

“…Liver kinase 1 is a tumor suppressor gene widely expressed in all tissues, and is involved in cell polarity, cell motility, protein translation, energy metabolism and various signal transduction pathways (26)(27)(28)(29). LKB1 can phosphorylate downstream AMPK at threonine 172 (30)(31)(32).…”

The Serine/Threonine Kinase STK11 Promotes Shigella flexneri Dissemination through Establishment of Cell-Cell Contacts Competent for Tyrosine Kinase Signaling

“…In an RNA interference (RNAi) screen for host factors required for S. flexneri infection, we identified the cell polarity kinase STK11 (also known as LKB1) as a serine/threonine kinase required for bacterial dissemination. Interestingly, the genome of HeLa cells has undergone substantial rearrangements, and the locus encoding STK11 is no longer present in this cell line (24). Accordingly, STK11 expression was detectable by Western blot analysis in HT-29 cells but not in HeLa229 cells (see Fig.…”