Abstract
HOXA9 functioning as a transcription factor is one of the members of HOX gene family, which governs multiple cellular activities by facilitating cellular signal transduction. In addition to be a driver in AML which has been widely studied, the role of HOXA9 in solid tumor progression has also received increasing attention in recent years, where the aberrant expression of HOXA9 is closely associated with the prognosis of patient. This review details the signaling pathways, binding partners, post-transcriptional regulation of HOXA9, and possible inhibitors of HOXA9 in solid tumors, which provides a reference basis for further study on the role of HOXA9 in solid tumors.
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Background
Homeobox genes were firstly discovered when identifying the characterization of several functional genes in Drosophila development [1]. Members of the HOX family have a well-conserved DNA binding homeodomain which have indispensable roles in managing the expression of genes during early development [2]. At present, 39 HOX genes were identified and classified into four clusters including HOXA cluster, HOXB cluster, HOXC cluster, and HOXD cluster [ In addition to be regulated at transcriptional levels, many post-transcriptional events including microRNAs, long non-coding RNAs, and epigenetic modification could also determine HOXA9 protein level and function. These post-transcriptional events show alternative aspects of HOXA9 regulation and might offer novel therapeutic opportunities in cancer treatment. MicroRNAs (miRNAs) are a type of small and short RNAs which have critical roles in regulating the post-transcriptional of target genes. miRNAs are associated with the etiology mechanism of multiple diseases including asthma, allergic rhinitis, and tumor [77]. Retrieval of the published literature on HOXA9, we found that many documents involved the role of HOXA9 regulated by multiple microRNAs in various tumors (Table 2). In addition, we observed that study about HOXA9 as a target of these miRNAs in osteosarcoma is more than in other solid tumors, prompting that HOXA9 might implement a crucial role in osteosarcoma regulated by miRNAs. Research reported that HOXA9 was identified as a downstream target of miR-1294 in osteosarcoma [78]. Furthermore, HOXA9 as a direct target of miR-429 [54], miR-873 [79], miR-652 [165]. PD 0332991 (palbociclib), is a selectively and potently inhibitor of CDK4 and CDK6. The research performed by Yang et al. showed that PD 0332991 induced apoptosis of AML cells through inhibiting HOXA9 expression and reducing its target PIM1expression [166]. The role of PD 0332991 in solid tumors such as breast cancer [167], lung cancer [168], and glioma [169] has been widely studied. Multiple clinical trials about palbociclib treated in various tumors such as breast cancer, ovarian cancer, Pancreatic Ductal Adenocarcinoma. Besides, other CDK4/6 inhibitors such as Abemaciclib [170], Ribociclib [171], Lerociclib [172], Trilaciclib [173], Dinaciclib [174], and SHR6390 [175] are also being adopted in clinical testing. This review described the structures of HOXA9 and its expression and diverse roles in solid tumors. The signaling pathways, post-transcription of modification, potential inhibitors, and binding partners of HOXA9 were presented. Although HOXA9 is a promising therapeutic target for AML and solid tumors, some issues need to be addressed. HOXA9 functioning as an oncogene or suppressor gene mainly depends on the heterogeneity of tumors. It is a challenge for us to investigate the mechanism of HOXA9 in tumors, especially in using HOXA9 inhibitors. In addition, the inhibitors of HOXA9 play a crucial role in tumor therapy through indirectly regulation of HOXA9 expression, no directly small molecular inhibitors targeting HOXA9 are developed at present. Therefore, the development of HOXA9 inhibitors is a topic needed to be focused on. What’s more, researches about HOXA9 in tumors were mainly focused on the miRNA, lncRNA, and methylation, while the mechanism is not deep enough. Further detailed study on the mechanistic roles of HOXA9 in tumors are required in the near future.
Post-transcriptional regulation of HOXA9
HOXA9 regulated by microRNAs
Conclusions
Availability of data and materials
Not applicable.
Abbreviations
- AML:
-
Acute myeloid leukemia
- miRNAs:
-
MicroRNAs
- ncRNAs:
-
Non-coding RNAs
- GBM:
-
Glioblastoma
- SC:
-
Stem cell
- CRC:
-
Colon cancer
- NPC:
-
Nasopharyngeal carcinoma
- cSCC:
-
Cutaneous squamous cell carcinoma
- NSCLC:
-
Non-small cell lung cancer
- HIF-1:
-
Hypoxia-inducible factor
- pVHL:
-
Hippel-Lindau tumor suppressor gene
- HNSCC:
-
Head and neck squamous cell carcinoma
- JAK-STAT:
-
Janus kinase-signal transducer and activator of transcription
- ATAC-seq:
-
Transposase-accessible chromatin using sequencing
- PH:
-
Pleckstrin homology
- TSC1/2:
-
Tuberous sclerosis complex 1 and 2
- S6K1:
-
Ribosomal protein S6 kinase
- 4E-BP:
-
EIF4E binding protein 1
- KDM3:
-
Lysine demethylase 3
- MS:
-
Mass spectrometry
- LSCs:
-
Leukemic stem cells
- TNBC:
-
Triple-negative breast cancer
- WDR5:
-
WD-40 repeat protein 5
- H3K9me2:
-
Lysine methyltransferase (KMT) di-methylates lysine 9 of histone H3
- BET:
-
Bromodomain and extra-terminal
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This work was supported by Grants from the National Natural Science Foundation of China (Grant No. 82173201, 82272758), the Natural Science Foundation of Hunan Province (No. 2021JJ30422), Hunan Cancer Hospital Climb Plan (2020NSFC-A001, 20210405-1001), and Scientific Research Project of Hunan Provincial Health Commission (A202302088151, B202304127661). The authors received no financial support for the research, authorship, or publication of this article.
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Tang, L., Peng, L., Tan, C. et al. Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential. Cancer Cell Int 22, 349 (2022). https://doi.org/10.1186/s12935-022-02767-9
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DOI: https://doi.org/10.1186/s12935-022-02767-9