IDENTIFICATION OF NOVEL TRANSCRIPTIONAL MODULATORS OF ONCOGENESIS

Abstract

Regulation of telomere lengths has an important role in enabling unlimited proliferation. In healthy somatic cells, telomeres shorten after each cell division and if they reach a critically short length, cells enter senescence followed by crisis, and eventually, they undergo death. However, some cells can bypass through telomerase reactivation. Telomerase is a multi-subunit complex. Human telomerase reverse transcriptase (hTERT), the catalytic subunit, carries reverse transcription activity to elongate telomeres. It can also regulate cell proliferation-related genes. Hence, hTERT has been an attractive therapeutic target. In my studies, I performed a high-throughput small molecule screen using hTERT promoter-specific reporter cells. The screen for epigenetic modulators identified that SP2509, a lysine-specific histone demethylase 1 (LSD1) inhibitor, significantly decreased hTERT expression as well as telomerase activity. Intriguingly, the effect of SP2509 on hTERT expression and telomerase activity was specific to colorectal cancer. The inhibitory mechanism regulating hTERT expression by SP2509 was not LSD1 mediated. Drug target identification showed that pirin, a transcription co-regulator, was a target of SP2509. This study showed that hTERT expression could be regulated by a pirin-mediated complex and disruption of this complex by SP2509 could be a promising therapeutical strategy specifically in colorectal cancer.