Epigenetic Regulation

Background

Multiple mechanisms have been proposed for how tumor cells evade treatment, many of which focus on aberrant protein coding signaling pathways. An additional layer of regulation that is less explored includes epigenetic regulation. The targeted anti-cancer agent erlotinib is a small molecule inhibitor of the Epidermal Growth Factor Receptor (EGFR), a receptor that is overactive due to mutation in lung cancer patients. Acquired secondary mutations in EGFR are one of the mechanisms that drive erlotinib resistance – others are proposed but are not fully understood.

Research Areas

To overcome this lack of knowledge, the Kasinski Lab used a CRISPR/Cas screen containing small guide RNAs that target both miRNA-coding and protein-coding genes and determined that loss of a histone methyltransferase, KMT5C, is a key event that drives erlotinib resistance (Cancer Resarch 2022). Overexpression and knockdown validation studies support this novel role. Moreover, patient data suggest that KMT5C is reduced in multiple cancers and that the reduction correlates with poor overall survival. As a histone methyltransferase, KMT5C regulates the expression of multiple oncogenes and miRNAs, many of which were previously found to be elevated in erlotinib-resistant tumor samples, yet the mechanism for their upregulation was left unidentified. For the first time, the Kasinski lab has shown that KMT5C is a repressor of these pro-growth pathways, and that repression occurs through dynamic coordination of KMT5C and long non-coding RNAs (lncRNAs) that regulate the oncogenes. Briefly, KMT5C induced a repressive H4K20me3 mark on the gene encoding the lncRNA. The lncRNAs act as enhancers for downstream oncogenes, thus in the repressive state the lncRNA and the corresponding oncogene are not expressed. As a global epigenetic modulator, loss of KMT5C promotes simultaneous upregulation of multiple oncogenes through this mechanism. 

Additional work is being conducted in collaboration to identify the targets of KMT5C involved in this process, which we hypothesize to be dynamically regulated by KMT5C, opposed to the constitutive silencing of the telomers and pericentric regions of the genome by KMT5C. The Kasinski lab has evidence to suggest this is the case, and that the regulation is not based on the canonical series of events that firstly involve H3K9me3, followed by recruitment of HP1 and finally KMT5C.