HOXB13, a transcription factor of class B class, is located in the center of development genes, but appeared as a double -edged sword in human cancer. Although necessary for embryonic design and organogenesis dependent on androgens, its expression is often kidnapped or extinguished by epigenetic, mutation and post -translational events that drive initiation, progress and resistance to tumor therapy. In over twenty cancer, protein acts as oncogen or cancer suppressor, depending on the tissue context, partners’ interaction and mutation status.
Transcription control is the first layer of dysregulation. In prostate cancer, BRD4 binds two distal strengthening elements to deposit H3K27AC in the HOXB13 promoter, triggering overall hypertension that drives the genes of the cellular and nucleotide-metabolism nucleotide cycle. And vice versa, H3K27Me3 through EZH2 or YY1 HDAC4 silences locus in endometrial and glioma cancer, removing the brake in proliferation. CPG methylation adds another switch: silence HOXB13 hypermetic in kidney cancer and colon cancer, while focal hypomethilation strengthens its transcription in oral squamous cell. The newly recognized ~ 4.5 KB of the CPG island still modulates expression in closer colon tumors, emphasizing locus as an epigenetic battlefield.
After transcription, MRNA HOXB13 is edited by M6A. FTO desems 3 ‘UR, extending the MRNA half -life and increasing the WNT driven invasion in endometrial cancer. RNA RNA, such as Cirs-7 and LNCRNA, such as CCAT1 Sponge MIR-7 or MIR-17-5P, respectively, soothing micro-repression and raising HOXB13 protein levels. Single nucleotide polymorphism, RS339331, increases the amplifier loop and HOXB13 covering in the RFX6 promoter, predisposing to prostate cancer in North Europe. These Potranskitic mechanisms increase the repertoire of tumors that can cooperate in the factor.
The protein level control is equally complicated. Creb binding protein of the LYS13 and LYS277 acetylts, stabilizing HOXB13 and increasing its correction of transcription based on an estrogen receptor in breast cancer. And vice versa, MTOR phosphorylictles THR8, THR41 and SER31, preparing protein for clothing and degradation via SKP2. Lysine mutations for arginine at acetylation Places imitate constitutive activation and correlate with castration resistant prostate cancer. Therefore, post-translation switches switch HOXB13 between pro-health modes of cancer and suppress cancer.
Hoxb13 rarely works alone. In the prostate epithelium it creates heterodimers from Meis1; The complex suppresses the AR signal by competing for chromatin and regulating the decor of the tumor suppressor. The mutations of the embryo line, such as G84E, Y80C or L144P, interfere with the MEIS1 bond, releasing HOXB13 to cooperate with AR-V7 fansion variants and activate the oncogenic zinc palera genes. In HOXB13 breast cancer, partners with CBP/P300 to amplify the Estrogen-Receptor signaling, while in stomach cancer it is associated with ALX4 to induce snail and trigger the epithelial transition of the epithelium-Mesenchymal. Interactions with the D1, NCOR/HDAC3 scraper and the hippo trail additionally expand their signal range.
HOXB13 directly occupies HOXC-AS3, ESR1 and IL-6 directly as a transcription factor, driving proliferation, invasion and angiogenesis. Activates the cascades of the RB/E2F and JNK/C-Jun, regulates IGF-1R via PI3K/AKT/MTOR and suppresses the Hippopopo signal by VGLL4. In hepatic cellar cancer, the high expression Hoxb13 correlates with an advanced and poor experience, while in stomach cancer low expression disease means an aggressive disease, emphasizing the roles depending on the context.
The clinical influence is already tangible. Immunohistochemistry Hoxb13 distinguishes paraganglioma Cauda Equina from Epndymom, and the combined dyeing HOXB13/P63 separates high -quality prostate cancer from urotelic cancer. The HOXB13/IL17B expression coefficient (breast cancer indicator) provides for a late recurrence in breast cancer-registor estrogen and prolonging tamoxifen after five years. HOXB13 transcripts in urine serve as non-invasive biomarkers for early detection of prostate cancer, while tissue levels stratify patients to inhibit AR or Bet-Bromodomen.
Therapeutically HDAC4 inhibitors, such as sodium butterran, restore HOXB13 repression in prostate cancers with negative AR. The Bet JQ1 antagonist displaces the BRD4 from the HOXB13 promoter, and DNMT inhibitors reverse CPG hypermetic in the colorectal cancer. Retinic acid or EZH2 lock reduces H3K27Me3 and reactivates tumor suppression via HOXB13. Decorin and CHD1 interfere with the HOXB13-AR or HOXB13-MEIS1 interface, limiting castration resistance. Phase II tests connecting BET and PI3K inhibitors use HOXB13 addiction in castration resistant prostate cancer.
Geographical and ethnic heterogeneity continues to shape clinical strategy. Founder G84E mutation It reaches 3.5 % of the carrier frequency in Finns and provides prostate cancer early, but is practically absent from East Asia. Screening guidelines now recommend dog tests at the age of 40 for G84E carriers, while multiplex panels containing HOXB13 together with BRCA2 and ATM improve risk forecasting in various populations. Moving forward, one -cell multicellular and spatial transcriptomics promises to map the HOXB13 network in cancer microenvils, informing about precise combinations that use its dualistic nature for the patient’s benefits.
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Reference to the journal:
Zhang, J., (2025) HOXB13 in cancer development: molecular mechanisms and clinical implications. . doi.org/10.1007/s11684-024-1119-X.