Abstract
In contrast to the intensely studied genetic and epigenetic changes that induce host cell transformation to initiate tumor development, those that promote the malignant progression of cancer remain poorly defined. As emerging evidence suggests that the hypoxic tumor microenvironment could re-model the chromatin-associated proteome (chromatome) to induce epigenetic changes and alter gene expression in cancer cells, we hypothesized that hypoxia-driven evolution of the chromatome promotes malignant changes and the development of therapy resistance in tumor cells. To test this hypothesis, we isolated chromatins from tumor cells treated with varying conditions of normoxia, hypoxia, and re-oxygenation and then partially digested them with DNase I and analyzed them for changes in euchromatin- and heterochromatin-associated proteins using an iTRAQ-based quantitative proteomic approach. We identified a total of 1446 proteins with a high level of confidence, including 819 proteins that were observed to change their chromatin association topology under hypoxic conditions. These hypoxia-sensitive proteins included key mediators of chromatin organization, transcriptional regulation, and DNA repair. Furthermore, our proteomic and functional experiments revealed a novel role for the chromatin organizer protein HP1BP3 in mediating chromatin condensation during hypoxia, leading to increased tumor cell viability, radio-resistance, chemo-resistance, and self-renewal. Taken together, our findings indicate that HP1BP3 is a key mediator of tumor progression and cancer cell acquisition of therapy-resistant traits, and thus might represent a novel therapeutic target in a range of human malignancies.
Highlights
Microenvironmental hypoxia is a hallmark of rapidly growing solid tumors
Recent research has uncovered many of the oncogenes and tumor suppressor genes that influence tumor development, but variation among cancer cell types means that it is an extremely challenging task to compile an exhaustive list of all the aberrant molecular events that can promote tumor formation and dissemination
Hypoxia appears to be a common driver of cancer cell evolution, as gas diffusion cannot supply solid tumors with sufficient oxygen as they progressively increase in size (Fig. 1)
Summary
Microenvironmental hypoxia is a hallmark of rapidly growing solid tumors. In order to overcome the growth restrictions. Tumor progression is thought to be driven by selective pressure on the cancer cells exerted by the hypoxic microenvironment, leading to the clonal evolution of many different cancer cell phenotypes within an individual patient This combination of increasing diversity and enhanced survival characteristics makes it progressively more difficult to kill all cancer cell types using a single therapeutic strategy. Emerging evidence suggests that hypoxia contributes to the development of cancer stem cells that exhibit enhanced capacity for self-renewal [6] Together, these data indicate a critical role for hypoxia-sensitive molecular pathways in promoting cancer progression that it may be possible to target with novel therapies in order to disrupt tumor growth [7].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
