Nuclear Envelope Regulation of Oncogenic Processes: Roles in Pancreatic Cancer

Abstract

Pancreatic cancer is an aggressive and intractable malignancy with high mortality. This is due in part to a high resistance to chemotherapeutics and radiation treatment conferred by diverse regulatory mechanisms. Among these, constituents of the nuclear envelope play a significant role in regulating oncogenesis and pancreatic tumor biology, and this review focuses on three specific components and their roles in cancer. The LINC complex is a nuclear envelope component formed by proteins with SUN and KASH domains that interact in the periplasmic space of the nuclear envelope. These interactions functionally and structurally couple the cytoskeleton to chromatin and facilitates gene regulation informed by cytoplasmic activity. Furthermore, cancer cell invasiveness is impacted by LINC complex biology. The nuclear lamina is adjacent to the inner nuclear membrane of the nuclear envelope and can actively regulate chromatin in addition to providing structural integrity to the nucleus. A disrupted lamina can impart biophysical compromise to nuclear structure and function, as well as form dysfunctional micronuclei that may lead to genomic instability and chromothripsis. In close relationship to the nuclear lamina is the nuclear pore complex, a large megadalton structure that spans both outer and inner membranes of the nuclear envelope. The nuclear pore complex mediates bidirectional nucleocytoplasmic transport and is comprised of specialized proteins called nucleoporins that are overexpressed in many cancers and are diagnostic markers for oncogenesis. Furthermore, recent demonstration of gene regulatory functions for discrete nucleoporins independent of their nuclear trafficking function suggests that these proteins may contribute more to malignant phenotypes beyond serving as biomarkers. The nuclear envelope is thus a complex, intricate regulator of cell signaling, with roles in pancreatic tumorigenesis and general oncogenic transformation.

Nuclear Dynamics and Chromatin Structure: Implications for Pancreatic Cancer

“…The nucleus is surrounded by the nuclear envelope, which is composed of two concentric bilayer membranes, an outer nuclear membrane (ONM) and an inner nuclear membrane (INM), which each possess a specialized set of proteins (Figure 1) [16,17]. These two membrane layers are separated by the nuclear envelope lumen, a space of 30-50 nm.…”

“…While the positions of individual chromosomes are not tightly fixed, each chromosome is reported to exhibit a somewhat consistent radial distance from the nuclear center. Further studies have illustrated that gene-poor chromosomes tend to be closer to the nuclear periphery and gene-rich chromosomes closer to the nuclear center, and that, within CTs, repressed genes are often at the nuclear periphery while activated genes are generally present closer to the nuclear center [17,168,169]. A refinement of the CT concept describes the presence of an interchromatin compartment, a series of channels between and pervading the CTs [163].…”

“…Nesprin-1 and -2 connect to actin filaments, Nesprin-1α and Nesprin-4 bind to microtubules via kinesin, and Nesprin-3 binds to Plectin, allowing the potential for Nesprins to indirectly interact with all cytoskeletal networks [191][192][193][194][195]. The C-terminal SUN domains of the SUN proteins interact with the C-terminal domains of Nesprin proteins [196], while the SUN protein N-termini cross the INM, allowing the transmittal of mechanosignals to the nuclear lamina and nuclear pore complex, culminating in changes in chromatin organization and gene expression [17,22,197]. Although SUN proteins were thought to be primarily redundant in function, a recent study found that SUN2 promoted the activation of RhoA, a key regulator of the actin cytoskeleton, whereas SUN1 acted in competition with SUN2 to inhibit RhoA activity [198].…”