Investigator
Unsw Sydney
Investigation of Transcriptome Patterns in Endometrial Cancers from Obese and Lean Women
Endometrial cancer is the most common gynaecological malignancy in developed countries. One of the largest risk factors for endometrial cancer is obesity. The aim of this study was to determine whether there are differences in the transcriptome of endometrial cancers from obese vs. lean women. Here we investigate the transcriptome of endometrial cancer between obese and lean postmenopausal women using rRNA-depleted RNA-Seq data from endometrial cancer tissues and matched adjacent non-cancerous endometrial tissues. Differential expression analysis identified 12,484 genes (6370 up-regulated and 6114 down-regulated) in endometrial cancer tissues from obese women, and 6219 genes (3196 up-regulated and 3023 down-regulated) in endometrial cancer tissues from lean women (adjusted p-value < 0.1). A gene ontology enrichment analysis revealed that the top 1000 up-regulated genes (by adjusted p-value) were enriched for growth and proliferation pathways while the top 1000 down-regulated genes were enriched for cytoskeleton restructure networks in both obese and lean endometrial cancer tissues. In this study, we also show perturbations in the expression of protein coding genes (HIST1H2BL, HIST1H3F, HIST1H2BH, HIST1H1B, TTK, PTCHD1, ASPN, PRELP, and CDH13) and the lncRNA MBNL1-AS1 in endometrial cancer tissues. Overall, this study has identified gene expression changes that are similar and also unique to endometrial cancers from obese vs. lean women. Furthermore, some of these genes may serve as prognostic biomarkers or, possibly, therapeutic targets for endometrial cancer.
The constitutively active form of a key cholesterol synthesis enzyme is lipid droplet-localized and upregulated in endometrial cancer tissues
Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we examined its lipid droplet-localized pool using complementary immunofluorescence and cell fractionation approaches and found that it exclusively comprises the truncated enzyme. This partitioning is facilitated by the loss of an endoplasmic reticulum-embedded region at the SM N terminus, whereas the catalytic domain containing membrane-associated C-terminal helices is spared. Moreover, we determined multiple amphipathic helices contribute to the lipid droplet localization of truncated SM. Taken together, our results expand on the striking differences between the two forms of SM and suggest upregulated truncation may contribute to SM-related oncogenesis.
