RT Journal Article
SR Electronic
T1 The Janus-faced role of KDM5B heterogeneity in melanoma: differentiation as a situational driver of both growth arrest and drug-resistance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.01.999847
DO 10.1101/2020.04.01.999847
A1 Heike Chauvistré
A1 Sheena M. Daignault
A1 Batool Shannan
A1 Robert J. Ju
A1 Daniel Picard
A1 Felix C. E. Vogel
A1 Stefanie Egetemaier
A1 Clemens Krepler
A1 Vito W. Rebecca
A1 Antonio Sechi
A1 Farnusch Kaschani
A1 Oliver Keminer
A1 Samantha J. Stehbens
A1 Renáta Váraljai
A1 Sabrina Ninck
A1 Qin Liu
A1 Xiangfan Yin
A1 Kirujan Jeyakumar
A1 Min Xiao
A1 Stefanie Löffek
A1 Linda Kubat
A1 Ivelina Spassova
A1 Sheraz Gul
A1 Sven Rahmann
A1 Susanne Horn
A1 Michael Ehrmann
A1 Annette Paschen
A1 Jürgen C. Becker
A1 Iris Helfrich
A1 Daniel Rauh
A1 Markus Kaiser
A1 Marc Remke
A1 Meenhard Herlyn
A1 Nikolas K. Haass
A1 Dirk Schadendorf
A1 Alexander Roesch
YR 2020
UL http://biorxiv.org/content/early/2020/04/01/2020.04.01.999847.abstract
AB Phenotypic intratumoral heterogeneity and temporal transitions between cell differentiation states represent major drivers of tumor fitness in melanoma. Expression of the histone H3K4 demethylase KDM5B/JARID1B follows a highly dynamic equilibrium across melanoma cells. When challenged for example with targeted or cytotoxic drugs, the intrinsically slow-cycling KDM5Bhigh cell state becomes initially enriched, whereas under persistent drug-exposure melanomas decrease KDM5B expression again to re-enter cell proliferation for long-term tumor repopulation. However, the exact role of KDM5B for tumor cell differentiation and fate remained elusive so far. Here, we show that melanoma fitness can be overcome by molecular enforcement of high KDM5B expression levels. KDM5B-up-scaled melanoma cells are transcriptionally reprogramed towards a differentiated melanocytic profile including a slow-cycling state. This effect can be phenocopied by a newly identified chemical compound also leading to decelerated tumor growth. Mechanistically, KDM5B represents a checkpoint for coordinating the differentiation phenotype of melanoma cells via transcriptional reprograming, cell cycle delay, and attenuation of cytokinetic abscission. These findings indicate that tumor plasticity per se, i.e. the necessity of cancer cells to dynamically switch between different cell cycling and differentiation states, represents an important oncologic process that can be chemically overcome.