title: HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome.
abstract: Melanoma is a highly lethal malignancy notorious for its aggressive clinical course and eventual resistance to existing therapies. Currently, we possess a limited understanding of the genetic events driving melanoma progression, and much effort is focused on identifying pro-metastatic aberrations or perturbed signaling networks that constitute new therapeutic targets. In this study, we validate and assess the mechanism by which homeobox transcription factor A1 (HOXA1), a pro-invasion oncogene previously identified in a metastasis screen by our group, contributes to melanoma progression. Transcriptome and pathway profiling analyses of cells expressing HOXA1 reveals upregulation of factors involved in diverse cytokine pathways that include the transforming growth factor beta (TGFβ) signaling axis, which we further demonstrate to be required for HOXA1-mediated cell invasion in melanoma cells. Transcriptome profiling also shows HOXA1's ability to potently downregulate expression of microphthalmia-associated transcription factor (MITF) and other genes required for melanocyte differentiation, suggesting a mechanism by which HOXA1 expression de-differentiates cells into a pro-invasive cell state concomitant with TGFβ activation. Our analysis of publicly available data sets indicate that the HOXA1-induced gene signature successfully categorizes melanoma specimens based on their metastatic potential and, importantly, is capable of stratifying melanoma patient risk for metastasis based on expression in primary tumors. Together, these validation data and mechanistic insights suggest that patients whose primary tumors express HOXA1 are among a high-risk metastasis subgroup that should be considered for anti-TGFβ therapy in adjuvant settings. Moreover, further analysis of HOXA1 target genes in melanoma may reveal new pathways or targets amenable to therapeutic intervention.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors: J
authors: J
authors: Wardwell-Ozgo
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors: T
authors: T
authors: Dogruluk
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors: A
authors: A
authors: Gifford
authors: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors: Y
authors: Y
authors: Zhang
authors: Institute for Applied Cancer Science, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors: T P
authors: TP
authors: Heffernan
authors: Department of Dermatology; Leiden University Medical Center, Leiden, The Netherlands.
authors: R
authors: R
authors: van Doorn
authors: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors: C J
authors: CJ
authors: Creighton
authors: 1] Institute for Applied Cancer Science, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA [2] Department of Genomic Medicine, Houston, TX, USA.
authors: L
authors: L
authors: Chin
authors: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors: K L
authors: KL
authors: Scott
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D009857:Oncogenes; D011379:Prognosis; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D059467:Transcriptome; D016896:Treatment Outcome; D000099261:Homeobox A1 Protein
chemical_list: D016207:Cytokines; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein