Cyclin E1 is dispensable for skin homeostasis and hyperplasia but is essential for carcinogenesis

Epidermal renewal needs tight control of the cell cycle and proliferation to face the continuous mutagenic pressure of UV light. Cyclin E1 is a key molecule in human epidermis, a main driver of the cell cycle and is frequently deregulated in cancer. Both Cyclin E1 and the homologue Cyclin E2 were shown generally dispensable for normal development and growth. However, their requirement for skin hyperplasia and squamous carcinogenesis was unknown.

We aimed to investigate the requirement of Cyclin E for skin homeostasis, hyperplasia and carcinogenesis.

We studied the skin and isolated keratinocytes in the absence of Cyclin E1. We analysed steady-state and hyperplastic defective epidermis and monitored carcinogen-induced skin carcinogenesis.

Cyclin E1-defective skin displayed normal histology and function. The epidermis displayed no differences in the capacity to boost proliferation after induction of hyperplasia. However, the lack of the cyclin strikingly overrode carcinogen-induced tumourigenesis. The absence of Cyclin E1 was not compensated by a rise of Cyclin A, another CDK2 potential regulator. Instead, Cyclin E2 was up-regulated in steady-state and hyperplastic skin, providing compensatory potential. However, we did not detect Cyclin E2 in most wild type tumours, especially in the less differentiated carcinomas.

Contrary to the situation in normal development, the results show that either Cyclin E1 or Cyclin E2 is essential for tumorigenesis. They also suggest that in the absence of Cyclin E1, Cyclin E2 serves homeostasis, whereas the oncogenic pathways suppress this compensation as an anti-tumour, self-preserve mechanism.