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UBC Theses and Dissertations

Characterization of SNF2 histone linker PHD RING helicase as a tumor suppressor gene in lung adenocarcinoma Sihota, Tianna S.


Lung cancer (LC) is the leading cause of cancer-related mortality globally, mainly due to its late diagnosis. Early detection and treatment of LC is therefore imperative to improve disease outcomes. With current LC screening guidelines, it is difficult to assess the importance of genetic predisposition as a predictor for LC risk. While several key genetic drivers of LC have been identified, their ability to be effectively targeted is limited. To identify novel genetic drivers of LC, our group performed integrative genomic analyses on never-smoker patients with lung adenocarcinoma (LUAD). This highlighted SNF2 Histone Linker PHD RING Helicase (SHPRH) as a candidate tumor suppressor gene in LUAD. SHPRH is located within a major lung cancer susceptibility locus and encodes an E3 ubiquitin ligase that facilitates DNA damage tolerance. This study aimed to evaluate the effect of SHPRH alteration on LUAD tumorigenesis and the tolerance of LUAD cells to DNA damage. LUAD datasets were analyzed to determine the association of SHPRH expression on survival outcomes, revealing that LUAD tumors frequently experience SHPRH copy number loss, which coincides with lower SHPRH expression and poorer survival outcomes. CRISPR/Cas9 knockout of SHPRH and a doxycycline-inducible system to express SHPRH in LUAD cell lines with varying SHPRH expression statuses was used to determine whether SHPRH expression affects their tumorigenic potential. It was observed that SHPRH re-expression in LUAD cells with inactivated SHPRH – not knockout or overexpression in cells without SHPRH disruption – reduces their colony growth and tumor formation. Further transcriptomic analyses to elucidate the mechanism that SHPRH may be acting in these cells highlighted several areas of interest for follow-up investigation. Finally, exploration into the influence of SHPRH expression on LUAD cellular fitness in response to DNA damaging lesions showed that it confers a protective effect that may be associated with alterations in cell cycle dynamics. Overall, this work provides phenotypic evidence for SHPRH expression having a tumor suppressive role in LUAD that may impact patient outcomes and the cellular response to DNA damage. Future work will focus on the implication of SHPRH expression and function to effectively predict, understand, and treat LUAD.

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