The HOXB13 gene, a pivotal component in developmental processes, exhibits a remarkably complex and often paradoxical role in the landscape of human cancer. Far from a simple binary function, its activity as either a promoter or suppressor of tumor growth is highly contingent upon the specific cellular environment, the presence of various interacting partners, and the nature of any genetic mutations it harbors. This intricate interplay necessitates a nuanced understanding to effectively leverage HOXB13 in clinical settings. The widespread dysregulation of HOXB13, occurring through epigenetic modifications, genetic mutations, and post-translational events, underscores its profound impact on cancer initiation, advancement, and resistance to treatment. With its involvement spanning more than twenty distinct cancer types, researchers are increasingly focused on unraveling its diverse molecular underpinnings to unlock new avenues for diagnosis and intervention.

The Intricate Regulation of HOXB13 in Cancer Progression

The expression and activity of HOXB13 are subject to sophisticated regulatory mechanisms across multiple molecular layers, each contributing to its context-dependent function in cancer. At the transcriptional level, its dysregulation is profound. In prostate cancer, the binding of BRD4 to specific enhancer elements leads to H3K27ac deposition at the HOXB13 promoter, triggering an overexpression that drives cell proliferation and nucleotide metabolism. Conversely, in endometrial carcinoma and glioma, EZH2-mediated H3K27me3 or HDAC4 recruitment by YY1 silences HOXB13, removing its tumor-suppressive brake and promoting uncontrolled cell growth. Epigenetic modifications, particularly CpG methylation, further modulate its expression, with hypermethylation leading to silencing in renal cell carcinoma and colon cancer, while focal hypomethylation amplifies its transcription in oral squamous cell carcinoma. The discovery of a novel upstream CpG island in proximal colon tumors highlights the dynamic epigenetic landscape surrounding this gene.

Beyond transcription, HOXB13 mRNA undergoes complex post-transcriptional modifications that influence its stability and translation. For instance, FTO demethylation of the 3' UTR of HOXB13 mRNA prolongs its half-life, thereby enhancing WNT-driven invasion in endometrial cancer. Furthermore, non-coding RNAs, such as circular RNAs like ciRS-7 and long non-coding RNAs like CCAT1, can act as sponges for microRNAs (e.g., miR-7 or miR-17-5p), alleviating their repressive effects on HOXB13 and consequently increasing its protein levels. A single-nucleotide polymorphism, rs339331, has been identified to increase enhancer looping and HOXB13 occupancy at the RFX6 promoter, which is associated with an increased susceptibility to prostate cancer in Northern European populations. These intricate post-transcriptional mechanisms significantly expand the array of cancers that can exploit HOXB13 for their pathological advantage.

HOXB13's Multifaceted Interactions and Clinical Promise

HOXB13 rarely operates in isolation; its impact is often amplified or modulated through interactions with various cellular partners, shaping its role in cancer. In prostate epithelial cells, HOXB13 forms heterodimers with MEIS1, a complex that inhibits androgen receptor (AR) signaling by competing for chromatin binding and up-regulating the tumor suppressor Decorin. However, specific germline mutations, such as G84E, Y80C, or L144P, disrupt this crucial MEIS1 binding, allowing HOXB13 to collaborate with oncogenic AR-V7 splice variants and activate zinc-finger genes that promote cancer growth. In breast cancer, HOXB13 partners with CBP/p300 to enhance estrogen-receptor signaling, while in gastric cancer, its interaction with ALX4 induces SLUG, initiating epithelial-mesenchymal transition. Its extensive signaling network further extends through interactions with cyclin D1, NCOR/HDAC3, and the Hippo pathway.

As a transcription factor, HOXB13 directly binds to the promoters of genes like HOXC-AS3, ESR1, and IL-6, driving processes critical for tumor progression, including proliferation, invasion, and angiogenesis. It activates key cellular cascades such as RB/E2F and JNK/c-Jun, up-regulates IGF-1R through the PI3K/AKT/mTOR pathway, and suppresses Hippo signaling via VGLL4. The clinical relevance of HOXB13 is already evident in diagnostics, where immunohistochemistry for HOXB13 helps differentiate cauda equina paraganglioma from ependymoma. The HOXB13/IL17B expression ratio (Breast Cancer Index) also serves as a predictor for late recurrence in estrogen-receptor-positive breast cancer, guiding extended tamoxifen therapy. Urinary HOXB13 transcripts show promise as non-invasive biomarkers for early prostate cancer detection, and tissue levels help stratify patients for targeted therapies. Therapeutic strategies targeting HOXB13 dysregulation are also emerging, including HDAC4 inhibitors, BET antagonists like JQ1, and DNMT inhibitors. These approaches aim to restore HOXB13's tumor-suppressive function or counteract its oncogenic activities. Geographic and ethnic variations in HOXB13 mutations, such as the G84E founder mutation in Finns, further emphasize the need for personalized medicine approaches. Future research utilizing single-cell multi-omics and spatial transcriptomics will continue to elucidate HOXB13 networks, paving the way for precise, context-specific cancer treatments.