Study reveals new regulator of prostate cancer metastasis

According to a Northwestern Medicine study published in Natural genetics.

The transcription factor, called HOXB13, is down-regulated in late-stage prostate cancer, triggering lipid biosynthesis and fueling cancer metastasis, according to Jindan Yu, MD, PhD, professor of medicine in the Division of of Hematology and Oncology and lead author of the study.

“HOXB13 has primarily been studied as a gene activator, but our study shows its primary function in transcriptional repression of lipid biosynthesis,” said Yu, who is also a professor of biochemistry and molecular genetics and a member of the Robert H. Lurie Comprehensive Cancer. Northwestern University Center.

HOXB13 is a prostate-specific protein that is highly expressed in the prostate during development. It stimulates androgen receptor (AR) function, which in turn helps prostate cells grow.

In prostate cancer, androgen hormones fuel uncontrolled cell growth and AR inhibitor treatments are the mainstay of care. However, most metastatic prostate cancers will eventually develop resistance to AR therapy, with the tumors eventually reducing their dependence on androgens by becoming more like stem cells. Previous studies have shown that while HOXB13 has a significant interaction with AR, their expression patterns do not match, with HOXB13 down-regulating while AR up-regulating as cancer progresses.

We thought something was missing about HOXB13 because the expression of HOXB13 and AR diverged.”


Jindan Yu, MD, PhD, lead study author

In the current study, scientists investigated the non-AR functions of HOXB13, finding that the transcription factor has an entirely distinct function in suppressing lipid biosynthesis, as part of the body’s normal defense against the cancer. However, as prostate cancer cells lose lineage and become resistant to treatment, they also lose expression of prostate-specific HOXB13, leading to a marked increase in lipid biosynthesis that can fuel cancer metastasis. .

“These cells forget who they are, which makes them resistant to AR inhibitors and may help cancer spread,” Yu said.

More than 30% of patients with treatment-resistant prostate cancer are negative for HOXB13 and therefore show elevated lipid biosynthesis in their cancers. Targeting this pathway could therefore prove useful in prolonging the survival of patients with advanced prostate cancer.

A drug called TVB-2640 that is already in clinical trials for breast and small cell lung cancer may help: the drug inhibits an enzyme essential to the lipid biosynthetic pathway, restoring some of that inhibition which acts as a natural defense against cell proliferation. and cancer.

“Now we just need to identify the optimal population in which to use this drug,” Yu said.

The study also made it possible to explain the curious case of G84Ea family change in HOXB13 which increases the risk of early-onset prostate cancer, but cancer severity was not different between patients with the G84E mutation and those without. The pathogenesis of the disease was previously unknown, but the current study found that the mutation disrupts inhibition of lipid biosynthesis, increasing prostate-specific protein levels. antigen (PSA), a biomarker sometimes used to screen for prostate cancer.

These results raise the possibility that the observed increased risk of early-onset prostate cancer associated with G84E may be an epidemiological trick rather than a true pathogenic mutation at the time of diagnosis, according to Yu and co-author William Catalona, ​​MD, a professor of urology and a pioneer in the use of PSA as a screening tool for prostate cancer. prostate.

“These patients have a family history, so they get screened frequently and at a younger age for prostate cancer,” Yu said. G84E patients provides management of the disease at an earlier stage, which could have offered protection because it cures the disease before it reaches a stage of resistance to treatment when G84E becomes pathogenic and promotes tumor metastasis.”

This work was supported by grants R01CA257446 and R01CA227918 from the National Institutes of Health, Prostate Cancer SPORE P50CA180995, Prostate Cancer Foundation grant no. 2017CHAL2008 and Department of Defense grant W81XWH-17-1-0578.

Source:

Journal reference:

Lu, X., et al. (2022) HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer. Natural genetics. doi.org/10.1038/s41588-022-01045-8.

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