The Constitutively Active Form of a Key Cholesterol Synthesis Enzyme Is Lipid Droplet-Localized and Upregulated in Endometrial Cancer Tissues

Authors

Hudson W Coates
Tina B Nguyen
Ximing Du
Ellen M Olzomer
Rhonda Farrell
Frances L Byrne
Hongyuan Yang
Andrew J Brown

Publication Date

5-1-2024

Journal

Journal of Biological Chemistry

Abstract

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.

Keywords

Female, Humans, Cell Line, Tumor, Cholesterol, Endometrial Neoplasms, Endoplasmic Reticulum, Gene Expression Regulation, Neoplastic, Lipid Droplets, Squalene Monooxygenase, Up-Regulation

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Associated Data

PMID: 38537696