(Press-News.org)
HOXB13, a B-class homeobox transcription factor, sits at the hub of developmental gene networks yet has emerged as a double-edged sword in human cancer. While indispensable for embryonic patterning and androgen-dependent organogenesis, its expression is frequently hijacked or extinguished by epigenetic, mutational and post-translational events that drive tumour initiation, progression and therapy resistance. Across more than twenty malignancies, the protein acts as either oncogene or tumour suppressor, depending on tissue context, interacting partners and mutational status.
Transcriptional control is the first layer of dysregulation. In prostate cancer, BRD4 binds two distal enhancer elements to deposit H3K27ac at the HOXB13 promoter, triggering overexpression that fuels cell-cycle and nucleotide-metabolism genes. Conversely, EZH2-mediated H3K27me3 or YY1-recruited HDAC4 silences the locus in endometrial carcinoma and glioma, removing a brake on proliferation. CpG methylation adds another switch: hypermethylation silences HOXB13 in renal cell carcinoma and colon cancer, whereas focal hypomethylation amplifies its transcription in oral squamous cell carcinoma. A newly recognised ~4.5 kb upstream CpG island further modulates expression in proximal colon tumours, highlighting the locus as an epigenetic battlefield.
Once transcribed, HOXB13 mRNA is subject to m6A editing. FTO demethylates the 3' UTR, prolonging mRNA half-life and boosting WNT-driven invasion in endometrial cancer. Circular RNAs such as ciRS-7 and lncRNAs like CCAT1 sponge miR-7 or miR-17-5p, respectively, relieving microRNA repression and elevating HOXB13 protein levels. A single-nucleotide polymorphism, rs339331, increases enhancer looping and HOXB13 occupancy at the RFX6 promoter, predisposing to prostate cancer in Northern Europeans. These post-transcriptional mechanisms enlarge the repertoire of tumours that can co-opt the factor.
Protein-level control is equally intricate. CREB-binding protein acetylates Lys13 and Lys277, stabilising HOXB13 and enhancing its co-activation of oestrogen-receptor-driven transcription in breast cancer. Conversely, mTOR phosphorylates Thr8, Thr41 and Ser31, priming the protein for SKP2-mediated ubiquitination and degradation. Lysine-to-arginine mutations at acetylation sites mimic constitutive activation and correlate with castration-resistant prostate cancer. Thus, post-translational switches toggle HOXB13 between tumour-promoting and tumour-suppressing modes.
HOXB13 seldom works alone. In prostate epithelium it forms heterodimers with MEIS1; the complex suppresses AR signalling by competing for chromatin occupancy and up-regulating the tumour suppressor Decorin. Germline mutations such as G84E, Y80C or L144P disrupt MEIS1 binding, liberating HOXB13 to cooperate with AR-V7 splice variants and activate oncogenic zinc-finger genes. In breast cancer, HOXB13 partners with CBP/p300 to amplify oestrogen-receptor signalling, whereas in gastric cancer it binds ALX4 to induce SLUG and trigger epithelial–mesenchymal transition. Interactions with cyclin D1, NCOR/HDAC3 and the Hippo pathway further expand its signalling reach.
As a transcription factor, HOXB13 directly occupies promoters of HOXC-AS3, ESR1 and IL-6, driving proliferation, invasion and angiogenesis. It activates RB/E2F and JNK/c-Jun cascades, up-regulates IGF-1R through PI3K/AKT/mTOR, and suppresses Hippo signalling via VGLL4. In hepatocellular carcinoma, high HOXB13 expression correlates with advanced stage and poor survival, whereas in gastric cancer low expression marks aggressive disease, underscoring context-dependent roles.
Clinical impact is already tangible. Immunohistochemistry for HOXB13 distinguishes cauda equina paraganglioma from ependymoma, and combined HOXB13/P63 staining separates high-grade prostate cancer from urothelial carcinoma. The HOXB13/IL17B expression ratio (Breast Cancer Index) predicts late recurrence in oestrogen-receptor-positive breast cancer and guides extension of tamoxifen beyond five years. Urinary HOXB13 transcripts serve as non-invasive biomarkers for early prostate cancer detection, while tissue levels stratify patients for AR-targeted or BET-bromodomain inhibition.
Therapeutically, HDAC4 inhibitors such as sodium butyrate restore HOXB13 repression in AR-negative prostate tumours. BET antagonist JQ1 displaces BRD4 from the HOXB13 promoter, and DNMT inhibitors reverse CpG hypermethylation in colorectal cancer. Retinoic acid or EZH2 blockade diminishes H3K27me3 and reactivates HOXB13-mediated tumour suppression. Decorin and CHD1 disrupt the HOXB13-AR or HOXB13-MEIS1 interface, limiting castration resistance. Phase II trials combining BET and PI3K inhibitors are exploiting HOXB13 addiction in metastatic castration-resistant prostate cancer.
Geographic and ethnic heterogeneity further shape clinical strategy. The G84E founder mutation reaches 3.5 % carrier frequency in Finns and predicts early-onset prostate cancer, yet is virtually absent in East Asians. Screening guidelines now recommend PSA testing from age 40 for G84E carriers, whereas multiplex panels incorporating HOXB13 together with BRCA2 and ATM refine risk prediction across diverse populations. Moving forward, single-cell multi-omics and spatial transcriptomics promise to map HOXB13 networks within tumour microenvironments, informing precision combinations that harness its dualistic nature for patient benefit.
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Date: Monday, August 11, 2025
Time:
‣ 15:00–16:00 (Beijing, China)
‣ 09:00–10:00 (CET, Europe/Swedish Time)
Speaker:
Prof. ...
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