LATS2 promoter hypermethylation and its effect on gene expression in human breast cancer

Abstract

Abstract. Tumor-specific promoter hypermethylation of large tumor suppressor, homolog 2 (LATS2), a tumor suppressor gene, has been investigated using methylation-specific polymerase chain reaction (MSP) assays in different types of human cancer producing conflicting results. The aim of the present study was to evaluate the methylation status of the LATS2 promoter region using bisulfite sequencing with a next generation sequencer for breast cancer. In the 11 patients enrolled in the present study, the LATS2 promoter methylation index (MI) was uniformly high in tumor and normal tissues of the breast (median, 84.0 and 87.4%, respectively). The presence of LATS2 promoter hypermethylation was confirmed in isolated tumor cells and normal epithelial cells using the magnetic-activated cell sorting method. In situ hybridization for LATS2 messenger RNA (mRNA) revealed that the mRNA expression of LATS2 was higher in normal epithelial cells, compared with tumor cells, however, it was not significantly associated with LATS2 MI. In 12 breast cancer cell (BCC) lines and two normal breast cell lines, the LATS2 promoter was uniformly hypermethylated with no correlation between the mRNA expression of LATS2 and the LATS2 MI. In addition, treatment of the BCC lines with a demethylating reagent had minimal effect on the mRNA expression of LATS2 in any of these cell lines. These results demonstrated that LATS2 hypermethylation was not involved in silencing the mRNA expression of LATS2 mRNA. The lower mRNA expression level of LATS2 in tumor cells, compared with normal epithelial cells, suggested the possible involvement of downregulation in the mRNA expression of LATS2 in the pathogenesis of breast cancer. Therefore, the conflicting results previously reported for LATS2 promoter methylation in different types of cancer, detected using MSP assays may be attributable to the low fidelity of the MSP assay. IntroductionLarge tumor suppressor, homolog 2 (LATS2), is a tumor suppressor gene implicated in the regulation of cell proliferation, migration and apoptosis via several cell signaling pathways, particularly the Hippo, p53 and LATS-LIM domain kinase-actin pathways (1). Classically, a tumor suppressor gene is inactivated by a somatic mutation or promoter hypermethylation. Previous human cancer genome projects have revealed the presence of LATS2 mutations in several types of human cancer, including breast cancer, however, its frequency is low at ~1% (2,3). Therefore, LATS2 mutations are unlikely to be important in the pathogenesis of the majority of breast cancer cases. By contrast, hypermethylation of the LATS2 promoter has been reported in a higher proportion of breast cancer (50%) (4), acute lymphoblastic leukemia (ALL) (24%) (5), astrocytoma (71.5%) (6), lung cancer (78.8%) (7), and nasopharyngeal cancer (36.7%) (8) cases, and the absence of LATS2 hypermethylation has been confirmed in normal breast tissues (4) and normal brain tissues (6). In addition, the association between LATS2 promoter hypermethylation and reduced messenger RNA ...

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“…This study found that LATS2 was down-regulated in gastric cancer. The finding was consistent with the previous study [44].…”

Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway

“…Consistently, our data showed that PAX6 can result in LATS2 hypermethylation. A recent study reported that LATS2 hypermethylation is not involved in silencing the mRNA expression of LATS2 mRNA 70 . However, the absence of LATS2 protein strongly correlates with promoter hypermethylation, where 91 of a total of 107 hypermethylated cases displayed the absence of protein 71 .…”

“…A recent study reported that LATS2 hypermethylation is not involved in silencing the mRNA expression of LATS2 mRNA. 70 However, the absence of LATS2 protein strongly correlates with promoter hypermethylation, where 91 of a total of 107 hypermethylated cases displayed the absence of protein. 71 Therefore, it is unclear whether LATS2 hypermethylation contributes to decreased LATS2 expression, and whether PAX6 promoting LATS2 hypermethylation is the key mechanism by which PAX6 regulates LATS2 protein expression.…”

The possible correlation between miR-762, Hippo signaling pathway, TWIST1, and SMAD3 in lung cancer and chronic inflammatory diseases

“…Previous research found that decreased MST1 transcript expression is correlated with methylation of its promoter region 27 . Additionally, methylation alterations frequently inactivate LATS2, making the Hippo signaling pathway unable to control caner development 33 .…”