Seminars in Cancer Biology

Hyaluronan-rich matrices are abundant in ECM and are involved in biological processes, such as cell growth and migration. Hyaluronan is synthesized by the hyaluronan synthase family of enzymes, HAS1, HAS2 and HAS3; the HAS1 and HAS3 genes give rise to different transcripts through alternative splicing, and the HAS2 gene to a non-coding RNA antisense transcript in addition to the protein-coding transcript. Biosynthesis of hyaluronan increases during inflammation and cancer and is regulated by cytokines and growth factors. In addition to extracellular hyaluronan-rich matrices, cytoplasmic and nuclear forms of hyaluronan have been detected in normal and pathological processes. Extra- and intra-cellular hyaluronan binds to hyaluronan binding proteins, such as CD44, RHAMM, CDC37 and USP17, affecting cellular behavior. Although neither the exact mechanisms by which hyaluronan is present in the intracellular compartments nor its function at these sites are currently understood, there are evidence that intracellular hyaluronan has important regulatory roles during cell cycle, cell motility, RNA translation and splicing, and autophagy.

Fig.1. Differential and conserved nucleosome occupancy at NSR and NDR during the cell cycle. In the upper panel, a model describing NDR and NSR. In the lower panel, signal-plots showing nucleosome occupancy spanning 3kb at NSR and NDR identified in G0/G1, S2, and G2/M phases. 0 indicates the middle of the NSR and NDR. Fig.2. miRNAs genome loci are overlapped with enhancers. Among 1871 annotated human miRNA precursor loci, 1263 miRNA genome loci are overlapped with enhancer marked by H3K4me1, and 1217 miRNA genome loci are overlapped with enhancer marked by H3K27ac, 1076 miRNA precursor loci partially or absolutely overlapped with the corresponding enhancer regions which are marked by both H3K27ac and H3K4me1. The blue circle means there are 478 highly conserved miRNA precursors marked by both markers. Fig.3. Tissue-specific enhancer marked in genome loci. The tissue-specific enhancer region is defined by the H3K27ac ChIP-seq peaks from Roadmap Data with macs2.0 default parameters. The top three lines of graphics mark the tissue-specific enhancer region and the miRNAs locus, such as miR-122 in liver, let-7g-5p in lung, miR-1-5P in skeletal muscle. The X axis shows the genome position; and the Y axis indicates H3K27ac ChIP-seq reads per million/base pair. The bottom line pictures show the miRNA expression in different tissues. The X axis presents the miRNAs expression level, meanwhile, the Y axis displays different tissue. Fig.4. NamiRNA miR-339 activates GPER1 expression in T47D cell. miR-339 were successfully transfected in breast cancer cell line T47D (Left panel). miR-339 can upregulates expression of targeted gene GPER1 compared to the negative control group (Right panel). Fig.5. NamiRNA ‒ enhancer ‒ gene activation network and cell identity loss The upper left panel indicates NSRs and NDRs are formed by the selective exclusion of histone during cell cycle. In the NDR regions, NamiRNA-enhancer-gene activation network exerts their function to govern the cell-specific gene expression pattern, in which Ago2 may serve as a guide. The upper right panel indicates the altered NSR-NDR distribution and NamiRNA-enhancer-gene activation network in a cancer cell, which drives the cell identity transition from normal cell to cancer cell during the cell cycle (the lower panel).