Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome

Abstract

Germ-line mutations of the LKB1 gene cause PeutzJeghers syndrome (PJS) characterized by mucocutaneous pigmentation, predisposition to benign hamartomas of the gastrointestinal tract and also to several types of tumors. However, somatic mutations of this gene are very rare. To examine inactivation of LKB1 by epigenetic mechanisms, we investigated a series of primary tumors and cancer cell lines, for hypermethylation a ecting the CpG island located in the 5' region of the LKB1 gene using Methylation-speci®c PCR (MSP). First, we screened 51 cancer cell lines. Only three colorectal and one cervical carcinoma cell lines were methylated at LKB1, and loss of the LKB1 transcript was demonstrated. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored LKB1 expression. To address the incidence of LKB1 epigenetic inactivation in primary tumors, we analysed colorectal, breast, gastric, pancreatic, thyroid, bladder and testicular carcinomas (n=195). Normal tissues from the mentioned organs were unmethylated in this region. Among the described tumors, only one colorectal carcinoma and three testicular tumors displayed LKB1 promoter hypermethylation. Further study of those histological types more commonly associated with PJS, demonstrated that LKB1 promoter hypermethylation was present in ®ve of 11 (45%) papillary breast carcinomas. Finally, in three patients with a strong family story suggestive of PJS disease, abnormal LKB1 methylation was found in four of 22 (18%) hamartomatous polyps lesions. Our ®ndings provide an alternative pathway for inactivation of the LKB1 tumor suppressor gene involving promoter hypermethylation. Oncogene (2000) 19, 164 ± 168.

Germinal center kinases in immune regulation

“…As a major upstream regulator of AMPactivated protein kinase subfamily members, including MARK/Par-1, LKB1 is involved in multiple aspects of cell function and has been linked to many human diseases especially malignant tumors. [63][64][65][66][67][68][69][70][71] Recently, LKB1 has been implicated in B-cell differentiation by mediating activation-induced cytidine deaminase-dependent remodeling of immunoglobulin genes, 72 as well as in T-cell differentiation by regulating TCR-mediated activation of phospholipase C gamma1 and AMP-activated protein kinase signaling. 73,74 LKB1 is directly phosphorylated by lymphocyte-specific protein tyrosine kinase and predominantly interacts with the adaptor protein LAT as well as phospholipase C gamma1 following TCR stimulation.…”

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

“…Epigenetic silencing of the LKB1 gene promoter was also reported in tumors associated with Peutz-Jeghers syndrome (Esteller et al, 2000). To investigate the mechanisms underlying LKB1 downregulation in esophageal cancer cells, we first determined whether LKB1 loss could be due to epigenetic silencing.…”

LKB1; linking cell structure and tumor suppression

“…In addition, some data suggest that LKB1 can be inactivated epigenetically in sporadic cancers. LKB1 promoter hypermethylation has been reported in nearly 50% of sporadic papillary breast cancers and 12% of testicular cancers, whereas LKB1 promoter hypermethylation appears uncommon or absent in other types of sporadic breast cancers, as well as colon, gastric and pancreatic cancers (Esteller et al, 2000). In addition, loss of LKB1 expression has been noted in sporadic endometrial cancers (Contreras et al, 2008), neuroendocrine lung cancers and pancreatic cancers (Sahin et al, 2003;Amin et al, 2008).…”