Yin Yang 1 Orchestrates a Metabolic Program Required for Both Neural Crest Development and Melanoma Formation

Abstract

Increasing evidence suggests that cancer cells highjack developmental programs for disease initiation and progression. Melanoma arises from melanocytes that originate during development from neural crest stem cells (NCSCs). Here, we identified the transcription factor Yin Yang 1 (Yy1) as an NCSCs regulator. Conditional deletion of Yy1 in NCSCs resulted in stage-dependent hypoplasia of all major neural crest derivatives due to decreased proliferation and increased cell death. Moreover, conditional ablation of one Yy1 allele in a melanoma mouse model prevented tumorigenesis, indicating a particular susceptibility of melanoma cells to reduced Yy1 levels. Combined RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and untargeted metabolomics demonstrated that YY1 governs multiple metabolic pathways and protein synthesis in both NCSCs and melanoma. In addition to directly regulating a metabolic gene set, YY1 can act upstream of MITF/c-MYC as part of a gene regulatory network controlling metabolism. Thus, both NCSC development and melanoma formation depend on an intricate YY1-controlled metabolic program. (D) Strategy used to conditionally ablate Yy1 in pre-migratory NCSCs. (E) Representative pictures of E13.5 control and Yy1 cko embryos. (F) Drawing representing the different NC derivatives analyzed. (G) Alcian Blue staining of control and Yy1 cko embryos. (H-J) Immunostaining (H) and quantification of Sox10 + (I) and Sox9 + (J) cells in E11.5 control and Yy1 cko BAs. (K) Immunohistochemistry for the neuronal marker NF in E13.5 control and Yy1 cko gut sections. (L and M) Immunostaining (L) and quantification (M) of Dct + melanocytes in E13.5 control and Yy1 cko embryos. (N and R) Immunostaining for Brn3a and NF (N) and quantification of Brn3a + (R) in E13.5 control and Yy1 cko DRGs. (O, P, and S) Immunostaining for Sox10 and NF (O), Fabp7 and NF (P), and corresponding quantification of Sox10 + cells (S) in the DRG. (Q) Quantification of DAPI + cells per DRG cross-section based on (N)-(P). Data are shown as mean ± SEM; n = 3 control and Yy1 cko embryos derived from at least two independent litters. p values were determined with unpaired Student's t test.

Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

“…Here, we offer a deep understanding of how MYC signaling can drive hepatocarcinogenesis without MYC amplification, a process that probably occurs through IGF2BP1, which is different from the conclusions of other studies on MYC amplification [48]. c-Myc has been extensively studied for its roles in the regulation of glucose, glutamine, and nucleotide metabolism [49,50], and Gao et al [28] recently indicated that increased c-Myc expression leads to enhanced SSP activation, an essential part of a metabolic switch, to facilitate HCC progression by transcriptionally upregulating the expression of multiple SSP enzymes. We found that c-Myc overexpression partially attenuated IGF2BP1 knockdown-induced decreases in the GSH/GSSG ratio, which was vital for SSP activation, but unfortunately not in GSH levels.…”

The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1

“…Accordingly, another study by Varum and colleagues showed that Yy1 cKO in mice affects neural crest (NC) development in a strict stage dependent manner. Early KO caused a reduction of multiple NC-derived lineages, whereas late KO (after embryonic day 11.5) resulted in no clear phenotypic difference compared to control ( Varum et al, 2019 ), showing a decreased dependency on YY1 regulated processes at later stages of neuronal development.…”

“…At first glance, YY1 does not seem essential for 3D chromatin organization, as the majority of its binding sites are close to transcription start sites (TSSs) and only a minority is located distal from regulated genes ( Gabriele et al, 2017 ; Varum et al, 2019 ; Zurkirchen et al, 2019 ). However, in YY1-haploinsufficient lymphoblastoid cell lines, the most differentially expressed genes were controlled by those distal YY1 binding sites ( Gabriele et al, 2017 ).…”

“…Surprisingly, early and late Yy1 cKO, caused similar changes in gene expression, which indicates that the decreased importance of YY1 during neuronal development does not coincide with a shift in YY1 target genes ( Zurkirchen et al, 2019 ). As YY1-regulated genes seemed to be mainly implicated in metabolic pathways and protein translation, influencing the cell cycle machinery indirectly in NPCs and NC ( Varum et al, 2019 ; Zurkirchen et al, 2019 ), Zurkirchen and colleagues hypothesized that a decreasing dependency on YY1 during cortical development is due to a decreased biosynthetic demand and decreased proliferation rate of cells at later stages of corticogenesis, making these cells less vulnerable to defects in these pathways.…”

“…For example, YY1 inhibits proliferation in pancreatic cancer through downregulation of SOX2 ( Zhang et al, 2017 ), while in melanoma, YY1 promotes tumor growth, and YY1 cKO prevents tumorigenesis in a melanoma murine model ( Varum et al, 2019 ). Interestingly, both early NC development and melanoma tumorigenesis seem to be particularly sensitive to alterations in the same metabolic processes that are regulated by YY1 ( Varum et al, 2019 ). Of note, next to YY1, YY2 can also be upregulated in cancer cells ( Kaufhold et al, 2017 ).…”