Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

Abstract

Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steadystate Crtc1 in thoracic tumors. In addition, we show that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1 null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona fide cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies.

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

“…As SIKs enzymatic activities are dependent on LKB1, it is anticipated that LKB1 deregulation impacts CRTC1 functional activities. This is supported by a recent study that indicated somatic loss of LKB1 in lung cancer is associated with CRTC1 activation (Komiya et al, 2010). However, questions still remain regarding the exact functional consequences of CRTC activation in tumorigenesis and whether CRTC activation is a key mediator in LKB1 loss.…”

“…Conversely, LKB1 knockdown in LKB1-expressing KYSE-70 cells led to a significant LYPD3 upregulation (Figure 5b). We also determined another target gene, NR4A2, in parallel, which is critical for the growth of lung cancer cells (Komiya et al, 2010). We found that NR4A2 shows similar changes in response to LKB1 modulation, but its expression is generally lower compared with LYPD3 (Supplementary Figure 9).…”

“…LKB1 was first recognized as a tumor-suppressor gene because its mutations cause Peutz-Jeghers syndrome, characterized by gastrointestinal hamartoma with an increased cancer risk (Giardiello et al, 2000;van Lier et al, 2010). This gene was later found to be a target for mutational inactivation in human malignancies including non-small cell lung carcinoma (Sanchez-Cespedes et al, 2002;Carretero et al, 2004;Ji et al, 2007;Matsumoto et al, 2007;Makowski and Hayes, 2008;Komiya et al, 2010;Mahoney et al, 2009), cervical carcinoma (Wingo et al, 2009), melanoma (Guldberg et al, 1999;Rowan et al, 1999) and others (Sanchez-Cespedes, 2007). The LKB1 gene encodes a serine/threonine kinase essential for the activation of AMPK (AMP-activated protein kinase) and 12 AMPK-related kinases; thus, it regulates multiple signaling pathways in cell growth, cell polarity and metabolism (Hezel and Bardeesy, 2008;Shackelford and Shaw, 2009;Luo et al, 2010).…”

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).…”

CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB–MYC involvement

“…Activation of CREB by CRTCs is harnessed by CRTC phosphorylation, which retains these coactivators in the cytoplasm (46). Therefore, constitutive CREB activity is manifest following inactivation of upstream regulatory kinases such as LKB1 that phosphorylate CTRCs (47)(48)(49). Indeed, several human esophageal tumor cell lines express reduced levels of LKB1 and CRTC1 phosphorylation relative to Het1 immortalized, normal esophageal epithelial cells (48).…”