​Nat Comm | Huang Haojie's team reveals a new mechanism of resistance in prostate cancer

Editor | Enzyme Prostate Cancer is one of the most common malignant tumors in men.

Androgen (Androgen)-Androgen receptor (AR) signal axis is the main driving force driving the progression of androgen receptor positive prostate cancer.

The androgen receptor promotes or inhibits the transcriptional activity of downstream genes by combining with androgen response element (ARE), which leads to the proliferation and metastasis of prostate cancer cells.

The androgen receptor signaling pathway plays a very important role in the occurrence and development of prostate cancer.
Therefore, androgen deprivation therapy (ADT) has become the main method for the treatment of prostate cancer.

However, treatment resistance and tumor progression often occur during ADT treatment.
The tumors in this period are called castration-resistant prostate cancer (CRPC).

Clinical data show that CRPC has a significant therapeutic effect on the second-generation androgen receptor signaling pathway inhibitors such as Enzalutamide (ENZ) and Abiraterone (ABI), indicating that the activation of AR signaling pathway is progressing in CRPC Still plays an important role.

However, CRPC has limited therapeutic effects on second-generation androgen receptor inhibitors (such as ENZ), and most patients quickly develop resistance.

Therefore, exploring the resistance mechanism of CRPC to enzalutamide and finding new therapeutic targets and strategies are current research hotspots.

Mayo Clinic (Mayo Clinic) Professor Huang Haojie's team and bioinformatics Professor Wang Liguo's team and Professor Wang Yuzhuo's team from the Vancouver Prostate Cancer Center in Canada and the center's director Professor Martin Gleave collaborated, the latest research results A noncanonical AR addiction drives enzalutamide resistance in prostate cancer was published in Nature Communications recently.

Through ChIP-seq, RNA-seq, PDX (patient-derived xenografts), patient specimen immunohistochemistry, and BET/p300 protein dual inhibitors and other technical methods, new mechanisms of enzalutamide resistance have been revealed and new treatments have been proposed.
Strategy.

The researchers found through AR ChIP-seq that in ENZ-resistant CRPC cells, not all AR protein binding to chromatin DNA is reduced, but some AR binding to chromatin DNA is increased—that is, AR binding Enhanced sites (Gained AR binding sites, gained-ARBS).

The researchers further found that in these Gained-ARBS sites not only there is no typical AR binding element ARE, but also no DNA binding motif of the pioneer factor FOXA1 on which AR routine activation depends; on the contrary, these Gained-ARBS sites The sites are enriched in CpG islands, and histone gene activation modification H3K27 acetylation (H3K27ac) is significantly increased.

These results suggest that in ENZ-resistant CRPC cells, a considerable part of AR-binding gene loci are activated through unconventional pathways.

The researchers found through RNA-seq that the CpG dinucleotide binding protein CXXC5 was significantly up-regulated in drug-resistant cells, and the up-regulated CXXC5 was mediated by TET2 to bind to the non-methylated CpG islands in the genomic DNA (CpG islands).
) To promote gene expression.

Further studies have found that AR transcripts bound to non-methylated CpG islands in drug-resistant cells up-regulate the expression of a series of tumor-promoting genes such as ID1; the high expression of these downstream genes is not only positively correlated with the mortality of CRPC patients, but can also promote cell proliferation.
And enzalutamide resistance.

Since the histone acetylation modification H3K27ac was significantly up-regulated in these atypically activated gene sites of AR, the researchers further demonstrated that enzalutamide-resistant prostate cancer organoids (Organoid) and patient-derived xenograft tumors (PDX) They were highly sensitive to NEO2734, a dual inhibitor NEO2734 that recognizes the transcriptional regulator BET and CBP/p300 protein that recognizes H3K27ac acetylation modification.

This finding not only reveals for the first time a new mechanism for CRPC cells to acquire acquired resistance to enzalutamide through atypical AR activation function, but also provides a new treatment strategy for this drug-resistant CRPC.

Enzalutamide (ENZ) resistance mechanism map link to the original text: https://doi.
org/10.
1038/s41467-021-21860-7 Plate maker: 11 related literature 1.
Yan Y, Ma J, Wang D , Lin D, Pang X, Wang S, Zhao Y, Shi L, Xue H, Pan Y, Zhang J, Wahlestedt C, Giles FJ, Chen Y, Gleave ME, Collins CC, Ye D, Wang Y, Huang H.
The novel BET-CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer.
EMBO Mol Med.
2019 Nov 7; 11 (11):e10659 Epub 2019 Sept 262.
Wu D, Yan Y, Wei T, Ye Z, Xiao Y, Pan Y, Orme JJ, Wang D, Wang L, Ren S, Huang H.
An acetyl-histone vulnerability in PI3K/AKT inhibition-resistant cancers is targetable by both BET and HDAC inhibitors.
Cell Rep.
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