Discovery of cancer vulnerabilities in gene expression regulation pathway

Abstract

Cancer is one of the leading causes of death and many researchers are working on combating cancer. Despite significant progress in cancer therapeutics, many cancers still lack targeted therapies and new ways to enhance the efficacy of current therapeutics are also in need. In this dissertation, I discovered (potential) cancer vulnerabilities in gene expression regulation pathway through two different approaches. In the first approach, based on analysis of large-scale genome-wide CRISPR screening data, C11orf53 and COLCA2, two previously unknown genes, were identified as vulnerabilities in transcription factor POU2F3-dependent small cell lung cancer cell lines and both were characterized as novel transcriptional co-activators for POU2F3. In the second approach, novel factors regulating cell surface level of mouse Qa-1 (homolog of human HLA-E protein), a molecule with immune-suppressive function and highly expressed by certain cancer cells, were identified through a genome-wide CRISPR screening. Among the hits, Ascc3 and Swi5 were found to be strong regulators and modulate Qa-1 at the transcription level. In summary, my work revealed potential cancer therapeutic targets and contributed to our understanding of gene expression regulation in the context of cancer.