Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies.

Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction.

Eukaryotic chromatin structure and dynamics play key roles in genomic regulation. In the current study, the secondary structure and intramolecular dynamics of human histone H4 (hH4) in the nucleosome core particle (NCP) and in a nucleosome array are determined by solid-state NMR (SSNMR). Secondary structure elements are successfully localized in the hH4 in the NCP precipitated with Mg . In particular, dynamics on nanosecond to microsecond and microsecond to millisecond timescales are elucidated, revealing diverse internal motions in the hH4 protein. Relatively higher flexibility is observed for residues participating in the regulation of chromatin mobility and DNA accessibility. Furthermore, our study reveals that hH4 in the nucleosome array adopts the same structure and show similar internal dynamics as that in the NCP assembly while exhibiting relatively restricted motions in several regions consisting of residues in the N-terminus, Loop 1, and the α3 helix region.

The dynamics of eukaryotic nucleosomes are essential in gene activity and well regulated by various factors. Here, we elucidated the internal dynamics at multiple timescales for the human histones hH3 and hH4 in the Widom 601 nucleosome core particles (NCP), suggesting that four dynamic networks are formed by the residues exhibiting larger-scale μs-ms motions that extend from the NCP core to the histone tails and DNA. Furthermore, despite possessing highly conserved structural features, histones in the telomeric NCP exhibit enhanced μs-ms dynamics in the globular sites residing at the identified dynamic networks and in a neighboring region. In addition, higher mobility was observed for the N-terminal tails of hH3 and hH4 in the telomeric NCP. The results demonstrate the existence of dynamic networks in nucleosomes, through which the center of the core regions could interactively communicate with histone tails and DNA to potentially propagate epigenetic changes.

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