Abstract:
Epigenetic alterations play an important part in carcinogenesis. Different biological responses, including cell proliferation, migration, apoptosis, invasion, and senescence, are affected by epigenetic alterations in cancer. In addition, growth factors, such as transforming growth factor-beta (TGFβ), are essential regulators of tumorigenesis. The molecular mechanisms of action of TGFβ are understood mainly through the canonical and non- canonical signal transduction pathways. Our understanding of the mechanisms that establish transient TGFβ stimulation into stable gene expression patterns remains incomplete. Epigenetic marks like Histone H3 modifications are directly linked with gene expression and play an essential role in tumorigenesis. However, the effects of TGFβ signaling on the genome wide H3K4me3 and H3K9me3 landscape remain unknown. In this study, we performed chromatin immunoprecipitation-sequencing (ChIP-Seq) to identify the genome-wide regions that undergo changes in H3K4me3 and H3K9me3 occupancy in response to TGFβ stimulation in cancer. We also show that TGFβ stimulation can induce acute epigenetic changes through the modulation of H3K4me3 and H3K9me3 marks at genes belonging to special functional categories in prostate cancer. TGFβ induces the H3K4me3 mark on its ligands like TGFβ, GDF1, INHBB, GDF3, GDF6, and BMP5, suggesting a positive feedback loop. Most genes were involved in the positive regulation of transcription from the RNA polymerase II promoter in response to TGFβ. Other functional categories were intracellular protein transport, brain development, EMT, angiogenesis, antigen processing, antigen presentation via MHC class II, lipid transport, embryo development, histone H4 acetylation, positive regulation of cell cycle arrest, and genes involved in mitotic G2 DNA damage checkpoints. On the other side, H3K9me3 occupancy increases in intronic regions after short-term (6h) TGFβ stimulation and in distal intergenic regions during long-term stimulation (24h). We also found evidence for a possible association of SLC transporters with the H3K9me3 mark in the presence of TGFβ during tumorigenesis. The epigenetic mechanisms-mediated regulation of gene expression by TGFβ was concentrated at promoters rich in SRY and FOXJ3 binding sites. Our results point toward a positive association between the oncogenic function of TGFβ and the H3K9me3 mark and provide a context for the role of H3K9me3 in TGFβ-induced cell migration and cell adhesion. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3. Our results link TGFβ stimulation to acute changes in gene expression through an epigenetic mechanism. These findings have broader implications on epigenetic bases of acute gene expression changes caused by growth factor stimulation.
