Chromatin and Cancer: Implications of Disrupted Chromatin Organization in Tumorigenesis and Its Diversification

SIMPLE SUMMARY: Human DNA is ~2 m long, but is efficiently packaged in cell nucleus that is a million times smaller. The concerted action of several enzymes enables this packaging through hierarchical folding of DNA. These enzymes deposit unique marks on the DNA and DNA-binding proteins collectively called the histone code. The histone code determines when and how a segment of DNA will open and be expressed. Pathogenic changes or mutations in the proteins produced by the cells alter this expression pattern. Here, we discuss how these mutations affect DNA packaging in cancer establishment, diversification, and therapeutic resistance. We also document available therapeutic approaches aimed at DNA packaging in cancer and the direction in which current research is heading. ABSTRACT: A hallmark of cancers is uncontrolled cell proliferation, frequently associated with an underlying imbalance in gene expression. This transcriptional dysregulation observed in cancers is multifaceted and involves chromosomal rearrangements, chimeric transcription factors, or altered epigenetic marks. Traditionally, chromatin dysregulation in cancers has been considered a downstream effect of driver mutations. However, here we present a broader perspective on the alteration of chromatin organization in the establishment, diversification, and therapeutic resistance of cancers. We hypothesize that the chromatin organization controls the accessibility of the transcriptional machinery to regulate gene expression in cancerous cells and preserves the structural integrity of the nucleus by regulating nuclear volume. Disruption of this large-scale chromatin in proliferating cancerous cells in conventional chemotherapies induces DNA damage and provides a positive feedback loop for chromatin rearrangements and tumor diversification. Consequently, the surviving cells from these chemotherapies become tolerant to higher doses of the therapeutic reagents, which are significantly toxic to normal cells. Furthermore, the disorganization of chromatin induced by these therapies accentuates nuclear fragility, thereby increasing the invasive potential of these tumors. Therefore, we believe that understanding the changes in chromatin organization in cancerous cells is expected to deliver more effective pharmacological interventions with minimal effects on non-cancerous cells.