A non-canonical tumor suppressive role for the long non-coding RNA MALAT1 in colon and breast cancers

Long noncoding RNAs (lncRNAs) constitute one of the largest classes of transcripts and have been widely implicated in various diseases such as cancer. Increasing evidence suggests that several lncRNAs are dysregulated and play critical roles in tumorigenesis. LncRNAs can be regulated by key oncogenes and tumor suppressors, adding complexity to the intricate crosstalk between protein coding genes and the noncoding transcriptome. In our study, we investigated the effect that dysregulation of the key tumor suppressor PTEN has on the noncoding transcriptome. We identified the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) as a target of PTEN and find that this regulation is conserved in both human and mouse as well as with both chronic and acute PTEN dysregulation. We show that this regulation is at least in part microRNA (miRNA)-dependent, and characterize the miRNAs that may be mediating this crosstalk. In summary, we establish and characterize a non-canonical PTEN-microRNA-MALAT1 axis that regulates tumorigenesis and describe for the first time that the MALAT1 lncRNA possesses novel tumor suppressive properties in colon and breast cancers. What's new? Long noncoding RNA (lncRNA) transcripts serve critical roles in biological processes. As a consequence, their dysregulation is implicated in various diseases, including cancer. In this investigation of tumorigenic effects of the noncoding transcriptome, the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was identified as a PTEN tumor suppressor target, with its regulation occurring in a microRNA-dependent manner. In colorectal and breast cancer patients, MALAT1 and PTEN transcripts are downregulated and associated with reduced survival. Meanwhile, in colon and breast cancer cells, MALAT1 knockdown was associated with enhanced migration and invasion capabilities. The findings offer insight into the context-specific tumor-associated characteristics of lncRNAs.