Modelling the microtubule: towards a better understanding of short-chain fatty acid molecular pharmacology

Abstract

Systems biology combines experimental data with computational modelling to describe complex biological mechanisms and pathways. Short-chain fatty acids (SCFAs-chemopreventive compounds produced in the colon lumen) impair microtubule (MT) function in colon cancer cells by altering the relative expression of β-tubulin isotypes. The β-tubulin isotype composition along MT fibres is believed to contribute to a "tubulin code" defining which microtubule-associated proteins (MAPs) and kinesins are recruited and the arrangement of tubulin post-transcriptional modifications (PTMs) along the fibre, which in turn dictate many critical cellular functions. SCFAs drive acetylation of many proteins by virtue of being histone deacetylase inhibitors (HDACi's). Known acetyl-proteins include transcription factors and cytoplasmic cytoskeletal keratins as well as histones. Disruption of the MT cytoskeleton is a prime target of many cancer therapies including anti-microtubule drugs (AMD). This review focuses on SCFAs as HDACi's and how they might affect tubulin dynamics, modifications and isotypes. It discusses the evolution of mechanistic models that have helped improve understanding of tubulin-MT structure and dynamics and how to develop these models, combined with those describing transcription and the cell cycle, could provide hypotheses for how SCFAs disrupt cytoskeletal function. The review demonstrates how systems biology could offer potentially novel ideas for therapies in the prevention and treatment of cancers through the continued development and elaboration of such models.