The LATS2/KPM Tumor Suppressor Is a Negative Regulator of the Androgen Receptor

Abstract

The androgen receptor (AR) is a member of the steroid receptor superfamily that plays critical roles in the development and maintenance of the male reproductive system and in prostate cancer. Actions of AR are controlled by interaction with several classes of coregulators. In this study, we have identified LATS2/KPM as a novel AR-interacting protein. Human LATS1 and LATS2 are tumor suppressors that are homologs of Drosophila warts/lats. The interaction surface of LATS2 is mapped to the central region of the protein, whereas the AR ligand binding domain is sufficient for this interaction. LATS2 functions as a modulator of AR by inhibiting androgen-regulated gene expression. The mechanism of LATS2-mediated repression of AR activity appears to involve the inhibition of AR NH2- and COOH-terminal interaction. Chromatin immunoprecipitation assays in human prostate carcinoma cells reveal that LATS2 and AR are present in the protein complex that binds at the promoter and enhancer regions of prostate-specific antigen, and overexpression of LATS2 results in a reduction in androgen-induced expression of endogenous prostate-specific antigen mRNA. Immunohistochemistry shows that LATS2 and AR are localized within the prostate epithelium and that LATS2 expression is lower in human prostate tumor samples than in normal prostate. The results suggest that LATS2 may play a role in AR-mediated transcription and contribute to the development of prostate cancer.

Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia

“…7 In this study, decrease of LATS2 expression was found to be correlated with several dismal prognostic features in ALL patients: low expression of LATS2 gene was more frequently observed among classical high-risk ALL groups (adults, T-cell phenotype, NCI poor risk and the presence of BCR-ABL fusion gene) and was also significatively and independently associated with a shorter DFS and OS in both adult and childhood ALL. These findings, together with the general expression of LATS2 in normal bone marrow, the emerging role of the LATS2 gene in other types of human cancer (ie, prostate and breast carcinoma), 3,8 and the confirmed role for LATS2 gene in mechanisms related to cellular homeostasis, such as apoptosis, genomic integrity and cell cycle regulation are supportive of LATS2 inactivation contributing directly to the clinical behavior of ALL…”

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

“…Several of these genes are known to have functional role associated with growth and replication, such as FOSB (a transcription factor involved in control of the cell cycle). This association with growth and replication also applies to a tumor suppressor gene, LATS1 [89], and the insulin-like growth factor 1 receptor [90]. The expression of one of these genes, CDC37, is mediated by the gene HSP90 [91], which is intimately involved in carcinogenesis [92] and has evolved under positive selection in some mammals [93].…”

LATS tumor suppressor: A new governor of cellular homeostasis

“…As such, loss of either of these genes leads to malignant phenotypes. [2][3][4][5][6][7][8][9][10] Therefore, understanding how LATS1 and LATS2 operate is key to understanding tumorigenesis. This review will explore what we know about how these tumor suppressors function, both as individual proteins and collectively, highlighting their potential redundant or distinct roles.…”

“…However, in this study, only implicated in soft tissue sarcomas, leukemia, astrocytoma and in cancers of the breast, prostate, lung, liver and esophagus. [2][3][4][5][6][7][8][9][10] Decreased expression of LATS2 is seen in prostate cancer tissues, 7 and levels of phosphorylated LATS1/LATS2 are reduced in tumor susceptible mst1/2 liver-specific knockout mice. 9 Classically, tumor suppressor loss-of-function occurs through mutations.…”