HOXA6

HOXA6 is a homeodomain transcription factor that specifies axial vertebral identity during embryogenesis, where targeted disruption in mouse causes a homeotic transformation of the seventh cervical vertebra to the first thoracic vertebra at its anterior expression boundary (PMID:7918106). Beyond development, HOXA6 regulates progenitor proliferation and self-renewal, as its enforced overexpression drives proliferation, colony formation, and factor-independent growth in multipotential hemopoietic progenitor cells (PMID:19157684). As a transcriptional regulator it acts directly on target promoters: HOXA6 binds the ZBTB12 promoter to activate its transcription, an axis that mediates the pro-tumorigenic effects of cancer-associated fibroblasts on gastric cancer cells (PMID:37708965). It also functions through protein partnership, physically interacting with and stabilizing PBX2 to cooperatively enhance gastric cancer migration, invasion, and metastasis (PMID:33535170). In cancer contexts HOXA6 shows context-dependent roles, promoting proliferation, EMT, and survival in colorectal cancer via Bcl-2 pathway regulation (PMID:29620285), yet acting as a negative regulator of the PI3K/Akt/ERK cascade to inhibit proliferation and promote apoptosis in clear cell renal cell carcinoma (PMID:31081053). HOXA6 is positioned within several regulatory circuits as both an effector and a target: it operates downstream of a TET1–SOX10 epigenetic axis to contribute to oxaliplatin-induced neuropathic pain (PMID:32428246), downstream of DDR1 to suppress ferroptosis in bladder cancer (PMID:40105492), and is itself transcriptionally silenced through EZH2-mediated H3K27me3 deposition recruited by the m6A-stabilized lncRNA TRERNA1 (PMID:40640307).

1. 1994 High

   Established HOXA6's foundational in vivo function by asking what role it plays in axial patterning; the knockout revealed it is required to specify vertebral identity at its anterior expression boundary.

   Evidence Targeted gene disruption in mouse with skeletal phenotype analysis

   PMID:7918106

   Open questions at the time

   • Does not identify direct downstream transcriptional targets in the developmental context
   • No molecular mechanism (DNA binding sites, cofactors) defined in vivo
2. 2009 Medium

   Extended HOXA6 function beyond development by testing its effect on blood progenitors; overexpression showed it can drive self-renewal and factor-independent proliferation.

   Evidence Retroviral overexpression in FDCP-Mix and Ba/F3 hemopoietic cell lines with colony and proliferation assays

   PMID:19157684

   Open questions at the time

   • Gain-of-function only; no loss-of-function or rescue
   • Downstream effectors not identified
   • Single lab
3. 2018 Medium

   Addressed whether HOXA6 contributes to tumor progression; bidirectional manipulation in colorectal cancer showed it promotes proliferation, invasion, and EMT while suppressing apoptosis via the Bcl-2 pathway.

   Evidence Overexpression and siRNA knockdown in CRC cell lines with multiple orthogonal functional and Western blot readouts

   PMID:29620285

   Open questions at the time

   • Direct transcriptional targets driving these phenotypes not identified
   • No in vivo validation
   • Single lab
4. 2019 Medium

   Tested HOXA6's role in a different tumor type and revealed a context-dependent, opposite function: it inhibits proliferation and promotes apoptosis by negatively regulating the PI3K/Akt/ERK cascade in renal carcinoma.

   Evidence Overexpression and shRNA knockdown in 786-O and 769-P cells with functional assays and pathway Western blots

   PMID:31081053

   Open questions at the time

   • Mechanism by which HOXA6 represses the pathway (direct vs indirect) not defined
   • Reconciliation with pro-tumor roles in other cancers unresolved
   • Single lab
5. 2020 Medium

   Defined an upstream regulatory input by asking how HOXA6 is induced in neuropathic pain; ChIP showed SOX10 binds the HOXA6 promoter, placing it downstream of a TET1–SOX10 epigenetic axis driving allodynia.

   Evidence RRBS, ChIP, siRNA knockdown, AAV overexpression, and behavioral assays in rat spinal dorsal horn

   PMID:32428246

   Open questions at the time

   • HOXA6 transcriptional targets in nociceptive neurons not identified
   • Single lab
6. 2021 Medium

   Identified a direct protein partner by asking how HOXA6 promotes metastasis; Co-IP showed it binds and stabilizes PBX2, with cooperative enhancement of invasion and metastasis.

   Evidence Co-immunoprecipitation, knockdown/overexpression, Transwell assays, and orthotopic mouse model in gastric cancer

   PMID:33535170

   Open questions at the time

   • Reciprocal interaction validation and mapping of binding interface not done
   • Mechanism of PBX2 stabilization unclear
   • Single lab
7. 2023 Medium

   Defined a direct transcriptional target by asking what genes HOXA6 activates; ChIP confirmed binding to the ZBTB12 promoter, establishing a HOXA6/ZBTB12 axis mediating CAF pro-tumorigenic effects.

   Evidence ChIP in 293T and CAFs, knockdown/overexpression, co-culture functional assays, and Western blot

   PMID:37708965

   Open questions at the time

   • Genome-wide target repertoire not defined
   • Whether ZBTB12 fully accounts for the phenotype unresolved
   • Single lab
8. 2025 Medium

   Established how HOXA6 itself is silenced in lung cancer; an m6A-stabilized lncRNA TRERNA1 recruits EZH2 to deposit H3K27me3 at the HOXA6 promoter, and HOXA6 re-expression rescues growth inhibition.

   Evidence m6A and RNA stability assays, EZH2/H3K27me3 ChIP, knockdown/overexpression, and xenograft in NSCLC

   PMID:40640307

   Open questions at the time

   • Direct HOXA6 targets mediating growth suppression in NSCLC not identified
   • Single lab
9. 2025 Medium

   Placed HOXA6 in a ferroptosis-regulatory circuit by asking how DDR1 protects bladder cancer cells; double-knockdown epistasis showed HOXA6 acts downstream of DDR1 to suppress ferroptotic death.

   Evidence siRNA double knockdown, ferroptosis inducers/inhibitors, biochemical ferroptosis markers, and xenograft in bladder cancer

   PMID:40105492

   Open questions at the time

   • Direct HOXA6 transcriptional targets controlling ferroptosis genes (GPX4, SLC7A11) not defined
   • No reconstitution
   • Single lab

• The unifying molecular basis of HOXA6's context-dependent and opposite roles across tumor types, and its direct genome-wide DNA-binding target repertoire, remain undefined.
• No genome-wide HOXA6 ChIP-seq target map in the corpus
• Mechanism distinguishing pro- vs anti-proliferative outcomes unresolved
• No structural model of HOXA6–DNA or HOXA6–PBX2 interaction