Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

Abstract

LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

“…We previously showed that loss of LKB1 expression resulted in dephosphorylation and nuclear entry of CRTC transcriptional coactivators and subsequent CREB-mediated transcriptional activation in both lung and esophageal cancer cells (41,42). LINC00473 was transiently upregulated in response to cAMP signaling in human ocular ciliary smooth muscle cells (43).…”

Proteomic and Functional Analyses Reveal the Role of Chromatin Reader SFMBT1 in Regulating Epigenetic Silencing and the Myogenic Gene Program*

“…ChIP-ChIP assays were performed as described previously (20). Briefly, cells were fixed with formaldehyde for 10 min at room temperature to cross-link the DNA to chromatin-associated protein complexes.…”

SelectiveIn VivoTargeting of Human Liver Tumors by Optimized AAV3 Vectors in a Murine Xenograft Model

“…Total RNA was extracted with the RNeasy Mini Kit (QIAGEN) and reverse transcribed using the Reverse Transcription System (Promega) as previously described (Gu et al, 2012), with modification. Realtime qRT-PCR amplification was carried out using SYBR Green PCR core reagents kit (Applied Biosystems), as previously described (Lin et al, 2013a).…”