Poster abstracts
Poster number 88 submitted by Kayla Lenshoek
Uncovering how lncRNA MALAT1 controls gene expression in cancer metastasis
Kayla Lenshoek (University of Michigan, Cellular and Molecular Biology), Brittany Bowman (University of Michigan, Biological Chemistry), Chase Weidmann (University of Michigan, Biological Chemistry )
Abstract:
Long noncoding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is linked to the progression of multiple cancer types. Upregulation of MALAT1 is often correlated with aggressive metastasis, and depletion of MALAT1 in cancer cells decreases metastatic potential. Interestingly, in healthy cells and wild-type mouse models, loss of MALAT1 has no effect on viability. The mechanisms by which MALAT1 promotes metastatic activity exclusively in cancer cells is not well understood, and MALAT1’s function in healthy cells is also unknown. Here we aim to uncover the mechanisms by which MALAT1 alters gene regulatory programs to promote metastasis in a lung cancer cell model. We create and validate A549 lung adenocarcinoma cell lines where CRISPR-based gene deletions and insertions alter MALAT1 expression or destabilize the MALAT1 transcript. We find that MALAT1 accumulates at high levels in nuclear speckles, but loss of MALAT1 does not strongly alter nuclear speckle formation. Increased MALAT1 expression promotes a mesenchymal phenotype, whereas reduction in MALAT1 expression promotes a more epithelial cell state. Further, we find that MALAT1 expression is inversely correlated with levels of EZH2 protein, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). Consequently, levels of the PRC2 epigenetic mark, Histone H3 Lysine 27 tri- methylation (H3K27me3) are inversely correlated with MALAT1 levels. In line with MALAT1’s pro-metastatic activity, we observe an upregulation in genes and pathways associated with cell adhesion, mobility, and mesenchymal cell identity in MALAT1 overexpression lines. These results are consistent with a model wherein MALAT1 reprograms cancer cells through reorganization of epigenetic marks to promote metastasis through mesenchymal gene programs.
Keywords: lncRNA, MALAT1, Epigenetics