Cholesterol Biosynthesis Blockers Put a PIN in Bladder Cancer

I

n 1996, molecular biologist Kun Ping Lu, a postdoctoral fellow in cell biologist Tony Hunter’s laboratory at the Salk Institute, was studying an essential mitotic kinase in yeast, called never in mitosis gene A (NIMA). Without NIMA, yeast can’t enter mitosis. In one of his experiments, he discovered an enzyme called PIN1, as NIMA’s interacting partner.¹

Tony Hunter is a cell biologist at the Salk Institute.

Tony Hunter

Since then, many scientists, including Lu, who now leads his own research group at Western University, have shown that PIN1 is overexpressed in different types of cancer and regulates many oncogenes and tumor suppressors. “PIN1 is a master cancer signal regulator,” Lu said. “So far, it has been shown to activate over 70 oncogenes and deactivate over 35 tumor suppressors.”

Recently, Hunter and his team explored PIN1 once again; this time, for its role in bladder cancer, one of the most common yet relatively understudied cancers in males. In a new study in Cancer Discovery, Hunter and his colleagues reported that PIN1 positively regulates sterol regulatory element-binding protein (SREBP2), a key transcription factor in the cholesterol biosynthesis pathway, in bladder cancer.² The researchers also showed that the simultaneous inhibition of PIN1 and cholesterol biosynthesis reduced bladder cancer cell proliferation both in cell lines and in mice, suggesting that this coinhibition strategy may be a viable therapeutic approach.

“I was surprised to learn the connection between PIN1 and SREBP2,” Hunter said. “I thought that PIN1 would act on a protein that is more directly involved in cell growth and proliferation pathways.”

Kun Ping Lu, a molecular biologist at Western University. Lu discovered PIN1 as a postdoctoral fellow in Hunter’s lab in 1996.

Kun Ping Lu

To understand PIN1’s role in bladder cancer, Hunter and his team analyzed changes in the RNA transcript levels in bladder cancer cells upon genetic ablation of PIN1. They performed gene-set enrichment analysis (GSEA), a computational method that can identify which molecular pathways are statistically different between two experimental conditions. The researchers observed that several genes associated with cholesterol metabolism were significantly downregulated when PIN1 was knocked out.

Out of these, Hunter and colleagues chose to pursue the gene that encodes for SREBP2 protein, as a previous study suggested that both PIN1 and SREBP2 may be involved in cholesterol synthesis in mice.³ The team validated the connection by showing that the levels of activated SREBP2 and its downstream targets were significantly lower in PIN1-knockout mice with bladder cancer.

A photo of scientist Daniel Eduardo Gomez. — Daniel Eduardo Gomez, a physician scientist at the National University of Quilmes, at a cancer patient advocacy conference in Amsterdam.
Daniel Eduardo Gomez

Daniel Eduardo Gomez, a physician scientist at the National University of Quilmes who was not involved in the study, said, “I don’t find the connection to SREBP2 surprising at all, actually. We already know that PIN1 positively regulates so many things that are upregulated in cancer—cholesterol biosynthesis is one of those things.”

Gomez’s team, led by cancer biologist Diego Mengual Gómez, has studied PIN1 in different cancers for decades. Although Daniel Eduardo Gomez was not surprised by PIN1’s connection to SREBP2, he thought that this new study would change the future of cancer therapy.

“What I found most interesting about this work is the combination of two mechanisms that promote tumor progression,” he said. “It’s opening the gates for better treatment, not just in bladder cancer, but in different cancers as well.”

According to Lu, who was not involved in this study, PIN1’s regulation of cholesterol pathways is likely not specific to bladder cancer, so the dual inhibition strategy can be translated across different types of cancer.