Chromatin, the complex of DNA and its intimately associated proteins, is the physiological form of eukaryotic genomes. Chromatin-mediated processes are thought to influence the cellular 'epigenetic landscape', including but not limited to, post-translational modifications (PTMs) of histone proteins and the incorporation or replacement of specialized histone variants into chromatin. Cancer is currently considered a disease of both genetic and epigenetic changes. While genetic factors have been correlated with progression of cutaneous malignancies, epigenetic factors related to histone PTMs and histone variants remain elusive. Recently, changes in global histone PTM levels have been reported to hold prognostic value in other neoplasms, such as breast, lung and prostate cancer. We hypothesize that formation of cutaneous malignancies occurs in a progressive manner and epigenetic mechanisms play a significant role in this process. Furthermore, we hypothesize that the identification of novel biomarkers has the potential to add another level of unique and critical information to the currently available prognostic markers, which are few for malignant melanoma (MM) and squamous cell carcinoma (SCC).
Three aims are proposed to test these hypotheses.
The first aim i s designed to identify histone-related changes in the development of MM via antibody based screening, as well as novel quantitative and combinatorial mass spectrometry (MS) approaches, using a panel of well-characterized melanoma cell lines.
The second aim i s geared towards identification of histone-related changes in SCC by similar antibody and MS approaches, again using a panel of relevant cell lines. In the third aim, we propose to apply the histone PTM and histone variant changes discovered in aims 1 and 2 to archival human patient samples of MM and SCC with the assistance of dedicated pathologists. Statistically significant histone-related biomarkers identified in tissue samples will in turn be considered for future studies designed to evaluate their diagnostic and prognostic value. The significance of this research lies in the fact that skin neoplasms is one of the most costly and rapidly expanding disease groups, and prognostic indicators for MM, with its high rates of mortality and SCC, with high rates of morbidity, are currently lacking. Therefore, the identification of novel epigenetic biomarkers that can prognosticate disease progression is critical.
Epigenetic mechanisms have now been clearly linked to tumorigenesis. However, the epigenetic factors related to histone biology in cutaneous neoplasms have not been explored. The identification of epigenetic biomarkers that can be used as diagnostic or prognostic indicators holds great value for the improvement of human health related to skin malignancies.
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