Researchers have identified a protein called ASH1L as a crucial factor that primes cancer cells to invade and colonize bone tissue . This discovery, detailed in the journal Nature Communications, offers a promising new target for future therapies aimed at preventing this often devastating complication.

The new research highlights ASH1L not just as a marker, but as an “epigenetic driver” of this spread. Think of ASH1L as a master switch operator for genes. It’s a histone methyltransferase, meaning it adds chemical tags called methyl groups to proteins called histones that package DNA . These tags influence which genes are turned on or off. The scientists found that ASH1L is genetically amplified and overexpressed in metastatic prostate cancer samples and that higher levels are associated with more advanced disease and worse outcomes for patients.

Experiments showed that reducing ASH1L levels in aggressive prostate cancer cells made them less able to invade tissues, a key step in metastasis. In mouse models, removing ASH1L from cancer cells using CRISPR dramatically suppressed the spread of tumors to the bone and significantly improved the survival of the mice. Conversely, increasing ASH1L in less aggressive cancer cells boosted their ability to grow tumors in bone.
The study also revealed the complex ways ASH1L helps cancer cells spread. It works with another protein called HIF-1α, which helps cells survive in low-oxygen environments often found in tumors. Together, ASH1L and HIF-1α turn on genes that promote metastasis. ASH1L’s role involves altering the chemical tags (H3K4me3 and H3K36me3) near these pro-metastasis genes, essentially making them more active.
Importantly, ASH1L doesn’t just affect the cancer cells themselves; it also changes the environment within the bone, making it more hospitable for incoming cancer cells. A critical part of this involves reprogramming immune cells called macrophages. ASH1L in cancer cells encourages local monocytes (a type of immune cell) to transform into “tumor-associated macrophages” (TAMs) that support tumor growth, specifically a subtype called lipid-associated TAMs.

The findings suggest that targeting ASH1L or the pathways it influences could be a new therapeutic strategy. Preclinical tests using an ASH1L inhibitor called AS-99 significantly suppressed bone metastases and prolonged survival in mice. Blocking macrophages or inhibiting HIF-1α also showed promise in reducing bone metastasis in mouse models driven by ASH1L.

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