Silencing effects of mutant RAS signalling on transcriptomes

Abstract

Mutated genes of the RAS family encoding small GTP-binding proteins drive numerous cancers, including pancreatic, colon and lung tumors. Besides the numerous effects of mutant RAS gene expression on aberrant proliferation, transformed phenotypes, metabolism, and therapy resistance, the most striking consequences of chronic RAS activation are changes of the genetic program. By performing systematic gene expression studies in cellular models that allow comparisons of pre-neoplastic with RAS-transformed cells, we and others have estimated that 7 percent or more of all transcripts are altered in conjunction with the expression of the oncogene. In this context, the number of up-regulated transcripts approximates that of down-regulated transcripts. While up-regulated transcription factors such as MYC, FOSL1, and HMGA2 have been identified and characterized as RAS-responsive drivers of the altered transcriptome, the suppressed factors have been less well studied as potential regulators of the genetic program and transformed phenotype in the breadth of their occurrence. We therefore have collected information on downregulated RAS-responsive factors and discuss their potential role as tumor suppressors that are likely to antagonize active cancer drivers. To better understand the active mechanisms that entail anti-RAS function and those that lead to loss of tumor suppressor activity, we focus on the tumor suppressor HREV107 (alias PLAAT3 [Phospholipase A and acyltransferase 3], PLA2G16 [Phospholipase A2, group XVI] and HRASLS3 [HRAS-like suppressor 3]). Inactivating HREV107 mutations in tumors are extremely rare, hence epigenetic causes modulated by the RAS pathway are likely to lead to down-regulation and loss of function.

Keywords: Class II tumor suppressor genes; DNA methylation; HRASLS gene family; HREV107; N-acyltransferase; O-acyltransferase; PLA2G16; PLAAT3; Phospholipase 1/2.