LncRNAs in human cancers: signal from noise

The human (cancer) genome is pervasively transcribed into a plethora of noncoding transcripts that are mostly not conserved, lowly expressed, and consistently derepressed in cancer. Long noncoding RNAs (lncRNAs) exert multiple key molecular functions in cancer, converging towards the regulation of epigenetic and post- transcriptional events. The lack of conservation and the low expression of lncRNAs are in striking contrast with their key role in all epigenetic and post-transcriptional processes in the cell, thus exposing the CC (conservation and concentration) paradox. LncRNAs are able to drive aberrant liquid–liquid phase separation in cancer in response to stressors. A better understanding of lncRNA-driven cancer aberrant compartmentalisation may lead to the development of new diagnostic and therapeutic tools and to the re-evaluation of basic concepts in RNA–protein interactions. Given the biochemical reaction stochasticity, the mechanisms leading to conservation of biological functions from noise are obscure. Pervasive transcription of nonconserved genomic regions generates lowly expressed cancer-specific long noncoding RNAs (lncRNAs). How such poorly expressed transcripts, often undetectable in normal tissues, consistently modulate the activity of multiple abundant proteins leading to cancer phenotypes is unclear. Biochemical reaction compartmentalisation in response to environmental oscillations through liquid–liquid phase separation (LLPS) may explain the emergence of order from molecular noise. LncRNAs contain repetitive sequences and as such contribute to molecular crowding and LLPS. We propose that lncRNAs mediate cancer stress signals by regulating aberrant LLPS. This emerging model and its consequences for stoichiometry and specificity may lead to the development of diagnostic tools and cancer-specific drugs. Given the biochemical reaction stochasticity, the mechanisms leading to conservation of biological functions from noise are obscure. Pervasive transcription of nonconserved genomic regions generates lowly expressed cancer-specific long noncoding RNAs (lncRNAs). How such poorly expressed transcripts, often undetectable in normal tissues, consistently modulate the activity of multiple abundant proteins leading to cancer phenotypes is unclear. Biochemical reaction compartmentalisation in response to environmental oscillations through liquid–liquid phase separation (LLPS) may explain the emergence of order from molecular noise. LncRNAs contain repetitive sequences and as such contribute to molecular crowding and LLPS. We propose that lncRNAs mediate cancer stress signals by regulating aberrant LLPS. This emerging model and its consequences for stoichiometry and specificity may lead to the development of diagnostic tools and cancer-specific drugs. refers to events that develop according to a plan (nonrandom) and thus are predictable. domains in proteins that do not contain a defined 3D structure in physiological conditions. They are often found at flexible linkers and loops connecting different domains. IDRs contain amino acids with high net charge and low hydrophobicity. refers to the finding that in most species, the genome is almost entirely transcribed, including areas before considered as purely regulatory. the property of a certain molecule to interact with selected partners. Specificity is often conferred by complementary 3D structural or sequence motifs. refers to a process fitting a random distribution and thus lacking a plan. is the numerical relationship between reactants and products in a chemical reaction.