My lab along other groups have previously emphasized the role of NSD proteins (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1)  as oncogenes. A growing number of studies link the NSD proteins to a variety of cancers. NSD1 is associated with acute myeloid leukemia, multiple myeloma, and lung cancer; NSD2 with the prostate cancer and multiple myeloma; NSD3 with both lung and breasts cancers along with the acute myeloid leukemia. NSD1-NUP98 translocation is associated with childhood acute myeloid leukemia with the NUP98-NSD1 fusion protein being an active H3K36 methylase. NSD1 is amplified in multiple myeloma, lung cancer, neuroblastomas and glioblastomas NSD2 has been found associated with the prostate cancer and multiple myeloma. Furthermore, the amplification of either NSD1 or NSD2 trigger the cellular transformation, initiating carcinogenesis events . Increased NSD2 activity was reported in the tumor proliferation in glioblastoma multiforms. Overexpression of NSD2 in myeloma cells leads to aberrantly high global levels of H3K36 di-methylation, accompanied by a decrease in levels of H3K27 methylation. In myeloma cells, NSD2 contributes to disrupt the chromatin structure and function contributing to the cellular transformation. In addition, NSD2 is found overexpressed in 15 different cancers and is associated with tumor aggressiveness or prognosis in most types of cancers. NSD3 is found amplified in breast cancer cell lines and primary breast carcinomas. Moreover, NSD3 is involved in lung cancer and the acute myeloid leukemia where NSD3 is fused with NUP98, similarly as NSD1.

Reducing NSDs activity through specific lysine-HMTase inhibitors appears promising to help suppressing cancer growth.

Over the last few months, we have been doing extensive virtually ligand screening of thousands of selected compounds along with a large number of HMTase assays. Here a short video of the top 10 molecules that tightly bind (inhibit) the histone lysine binding pocket of the SET domain of NSD2/MMSET/WHSC1, calculated in an “open-conformation (able to dock the histone lysine H3K36).

Here a video of my lovely baby girl Luna (9 months).

My lab is currently focused on epigenetic and cancers. Most particularly, we are interested in understanding the histone code and its implications in diseases, especially cancers. It is a really fascinating research areas.

Cancer initiation and progression are controlled by both genetic and epigenetic events. Both genetic and epigenetic alterations of transcriptional co-regulators are key features in carcinogenesis onset with aberrant gene functions and changes in gene expression levels.

Histone modifications along with other epigenetic mechanisms such as DNA methylation maintain gene activity states and are key in regulating a wide range of cellular processes. Alterations and deregulations in the function of enzymes that modify histones alter the array and levels of histone marks and ultimately affect the control of chromatin-based processes. It leads to dramatic changes in gene expression profiles, which eventually contribute to oncogenic transformation and the development of cancer.

Histones are the stage of multiple post-translational modifications. Specific residues on histones H2A / H2B, H3 and H4 can be modified by methylation (Lysine / Arginine), acetylation (Lysine), citrullination (Arginine), phosphorylation (Serine / Threonine), ubiquitination (Lysine), sumoylation (Lysine), ADP-ribosylation (Lysine), butyrylation (Lysine), propionylation (Lysine) and glycosylation (Serine / Threonine).

Amongst the array of covalent histone modifications, lysine methylation is one of the prominent signaling pathway in chromatin-regulatory mechanism. Lysine-histone methyltransferases (HMTases) are transcriptional co-regulators that target specific lysines on H3 and H4, and can transfer up to three methyl groups (Kme1, Kme2, and Kme3) on histone tails. Lysine methylation, or any of the other histone modifications, can have both activating and repressive functions on transcription events. All the covalent histone modifications contribute to finely regulating the diverse activities associated with the chromatin and may be referred as a language of covalent histone modifications or histone code that is still obscure.

One fascinating aspect of the regulation of the transcription lies in the ballet between histones modifiers “readers” and “writers”, both being regulated leading to various physiological output based on the cellular context. This appends complexity to our current limited understanding of gene transcription and its implication in human diseases.