Loss of IKK (inhibitor of nuclear factor B kinase-) upregulates EGFR signaling and contributes to the development of squamous cell carcinoma of the skin.
Disruptions in the delicate balance between keratinocyte proliferation and differentiation can contribute towards the development of squamous cell carcinoma (SCC) of the skin — a common human malignancy. It has been proposed that innate surveillants, molecules that promote terminal keratinocyte differentiation, exist in the skin to prevent carcinogenesis, but the conclusive identification of such proteins has not yet been achieved.
BRAND X
Inhibitor of nuclear factor B kinase- (IKK, encoded by CHUK) is a promising candidate whose downregulation in mice leads to hyperproliferation of the epidermis and promotes chemically induced skin SCC development. But does IKK loss cause SCC? New evidence suggests that this is indeed the case. The study, led by Yinling Hu and colleagues, used an inducible murine K15 promoter to obliterate Chuk specifically in the hair follicle keratinocytes of Chukflox/flox mice. By 4 months, all mice had developed skin tumours resembling chemically induced papillomas and malignant carcinomas and, importantly, all tumours demonstrated Chuk loss. Closer examination of the epidermis of mutant mice revealed hyperproliferation of hair follicle keratinocytes and reduced expression of the terminal differentiation marker filaggrin. Together, these data asserted that the tumorigenic effect of Chuk ablation is linked to the induction of proliferation and the concomitant inhibition of differentiation.
How was IKK functioning? Vital clues were provided by the observed upregulation of epidermal growth factor receptor (EGFR) activity in the IKK-null epidermis and the fact that both pharmacological and genetic inhibition of EGFR in IKK-null cells blocked proliferation and induced terminal differentiation. These observations suggested that keratinocyte homeostasis was governed by cross-talk between EGFR and IKK, but how were the two proteins communicating?
Prompted by the observation that IKK-null keratinocytes expressed higher levels of mature EGF and heparin-binding (HB) EGF and lower levels of EGF and HBEGF precursors than wild-type cells, the authors hypothesized that IKK somehow limited the production of mature EGF. Accordingly, mRNA levels of the Adam (a disintegrin and metalloproteinase) sheddases, which cleave EGF precursors to generate their active forms, were significantly upregulated in IKK-null cells. Intriguingly, transcriptional regulation of the Adams is controlled by EGFR signalling, and chromatin immunoprecipitation experiments showed that IKK exerted a double-pronged attack on this EGFR-driven circuitry by directly downregulating the activity of the Egf, and the Adam12, Adam17 and Adam19 promoters.
These data support a new innate surveillance role for IKK, without which control of keratinocyte proliferation and differentiation are compromised by deregulated EGFR activity, providing a signalling milieu conducive to tumour formation. Given that IKK downregulation has frequently been observed in human SCC, this study suggests that interference with EGFR might be a new therapeutic option for these patients.
Safia Ali Danovi
References
Liu, B. et al. IKK is required to maintain skin homeostasis and prevent skin cancer. Cancer Cell14, 212–225 (2008) | Article | PubMed |
(inhibitor of nuclear factor 
B kinase-
