MYC in mammalian epidermis: how can an oncogene stimulate differentiation?

Abstract

MYC in human epidermal stem cells can stimulate differentiation rather than uncontrolled proliferation. This discovery was, understandably, greeted with scepticism by researchers. However, subsequent studies have confirmed that MYC can stimulate epidermal stem cells to differentiate and have shed light on the underlying mechanisms. Two concepts that are relevant to cancer have emerged: first, MYC regulates similar genes in different cell types, but the biological consequences are context-dependent; and second, MYC activation is not a simple 'on/off' switch - the cellular response depends on the strength and duration of MYC activity, which in turn is affected by the many cofactors and regulatory pathways with which MYC interacts.

Figure 1. Effect of Myc activation on murine skin

H&E stained sections of back skin of K14MycER transgenic mice treated with (A) acetone (control) or (B) 4OHT for 4 days. IFE: interfollicular epidermis; SG: sebaceous gland; HF: hair follicle. (A) shows the normal appearance of the epidermis. (B) shows that activation of Myc results in thickening of the IFE, SG enlargement and HF abnormalities. Scale bar: 100 μm.

Figure 2. Concept of Myc induced terminal differentiation as a fail-safe mechanism to prevent uncontrolled proliferation of epidermal stem cells

Stem cells are often in a quiescent (nondividing state). Activation of Myc leads to stem cell proliferation. Sustained or high level Myc activation stimulates proliferating stem cells to enter the transit amplifying compartment and thereby initiate terminal differentiation.

Figure 3. Summary of the different effects of Myc on the epidermal stem cell compartment

In upper part of Figure red arrows denote events stimulated by Myc: exit from the stem cell compartment, transit amplifying cell proliferation and terminal differentiation along the sebocyte and interfollicular epidermal lineages. Myc antagonism by Rac/PAK2 and Lrig1 is shown in blue and results in inhibition of stem cell proliferation (via Lrig1) and inhibition of both proliferation and terminal differentiation (via Rac/PAK2). SC: stem cell; TA: transit amplifying cell; IFE: interfollicular epidermis; SG: sebaceous gland; HF: hair follicle. The lower part of the Figure illustrates the transcription complexes involved in stimulating Misu/NSun2 expression and repressing expression of cell adhesion and cytoskeleton genes. Myc mediated inhibition of cell adhesion is dependent on repression of gene expression via complex formation with Miz1. In contrast, expression of Misu, which is required for Myc induced stimulation of proliferation, is positively regulated by Myc.

Figure 4. Reduction in epidermal hemidesmosome number and size on activation of Myc

Transmission electron microscopy of the epidermal basement membrane zone of K14MycER transgenic (tg) and wild-type (WT) mice treated for 9 days with 4OHT. Arrows in WT panels indicate hemidesmosomes. The number and size of hemidesmosomes is reduced in transgenic epidermis (arrows). Scale bars: 200 nm (top 3 panels), 1 μm (bottom panel). Reproduced from reference with permission from the Company of Biologists.

Figure 5. Schematic summary of the interplay between Rac1 and Myc in regulating the epidermal stem and transit amplifying cell compartments

Rac1 is required to maintain the stem cell compartment, while Myc stimulates stem cells to become transit amplifying cells,,. There is evidence for mutual antagonism between the effects of Rac1 and Myc: Rac1 negatively regulates Myc via PAK2 phosphorylation; Myc decreases expression of the α6β4 integrin via a Miz1-dependent mechanism; and α6β4 can activate Rac1.

Figure 6. Chromatin modification by Myc

(A) Contribution of Myc to formation of condensed, silent chromatin (left hand box) and open, active chromatin (right hand box),,. MTase: methyltransferase; HDAC: histone deacetylase; HAT: histone acetyl transferase. Histones are shown as trimethylated (Me) in silent chromatin and acetylation (Ac) in active chromatin. (B) Changes in histone methylation during the transition from stem (SC) to transit amplifying (TA) to terminally differentiation (TD) epidermal cell. Levels of tri- (Me3), di- (Me2) and mono- (Me1) methylated histones are shown.