Crucial role of the transcription factors family activator protein 2 in cancer: current clue and views

Journal article

The migration of human populations toward extreme latitudes precipitated the evolutionary selection of genetic variants which yielded skin colour alterations that maximize the absorption of ultraviolet radiation (UVR) needed for Vitamin D3 synthesis. A prime example of this phenomenon is represented by loss-of-function (LOF) coding variants in the Melanocortin 1 receptor (MC1R) associated with the Red Hair Colour (RHC) trait characterized by red hair, fair skin, high naevus count, and poor tanning ability. The human RHC trait is facilitated by high amounts of phaeomelanin (red-yellow), and reduced eumelanin (black-brown), pigment in skin and hair due to diminished MC1R function. Importantly, the RHC trait is strongly linked to increased skin cancer risk, including melanoma, a highly aggressive form of cancer arising from pigment producing cells known as melanocytes. Despite these known associations, the mechanisms surrounding the impact of RHC on skin colour and cancer are poorly understood. More specifically, it is unclear how decreased MC1R signalling drives phaeomelanogenesis and increases melanoma susceptibility. In this thesis, I first use single-cell RNA-sequencing (scRNA-seq) to define the transcriptomes of murine melanocytes which are primarily phaeomelanotic, have MC1R-inhibition and mimic the human RHC trait, or eumelanotic, have active MC1R signalling. I then defined the ‘MC1R-inhibited Gene Signature (MiGS)’ which comprises a large set of previously unidentified genes that may be implicated in melanogenesis and oncogenic transformation. Using this new dataset, I further investigated one such candidate MiGS gene, Tbx3, which encodes a well-known anti-senescence transcription factor (TF) implicated in melanoma progression and showed that TBX3 can bind E-box and T-box elements to regulate genes associated with melanogenesis and senescence bypass. Furthermore, I show that TBX3, and its subfamily member TBX2, bind and regulate (B&R) unique target genes in melanoma despite the high degree of homology that exists between their DNA binding domains. Collectively, these results provide key insights into previously unidentified mechanisms by which individuals with the RHC phenotype produce phaeomelanin and are predisposed to melanoma

Authors: Jin, C; Luo, Y; Liang, Z; Li, X; Kołat, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Journal of Translational Medicine
• Volume: 21
• Issue: 1
• Pages: 371-371
• Article number: 371
• Publication date: 2023-06-08
• DOI: 10.1186/s12967-023-04189-1
• EISSN: 1479-5876
• ISSN: 1479-5876
• Language: English
• Keywords: Epigenetics; Gene; Mediator; Cancer; Transcription factor; Regulation of gene expression; Cancer research; Genetics; Transcription (linguistics); Cell biology; Computational biology; Carcinogenesis; Activator (genetics); Biology