Sehgal Poonam, Chaturvedi Pankaj
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Cancers (Basel). 2023 Jan 11;15(2):466. doi: 10.3390/cancers15020466.
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.
癌症的一个标志是细胞不受控制地增殖，这通常与基因表达的潜在失衡有关。在癌症中观察到的这种转录失调是多方面的，涉及染色体重排、嵌合转录因子或表观遗传标记的改变。传统上，癌症中的染色质失调被认为是驱动突变的下游效应。然而，在这里，我们对癌症的发生、多样化和治疗抗性过程中染色质组织的改变提出了更广泛的观点。我们假设染色质组织控制转录机制的可及性，以调节癌细胞中的基因表达，并通过调节核体积来维持细胞核的结构完整性。在传统化疗中，增殖的癌细胞中这种大规模染色质的破坏会诱导DNA损伤，并为染色质重排和肿瘤多样化提供一个正反馈回路。因此，这些化疗中存活下来的细胞对更高剂量的治疗试剂产生耐受性，而这些试剂对正常细胞具有显著毒性。此外，这些疗法诱导的染色质紊乱加剧了核脆弱性，从而增加了这些肿瘤的侵袭潜力。因此，我们认为，了解癌细胞中染色质组织的变化有望带来更有效的药理学干预措施，同时对非癌细胞的影响最小。
