The LKB1-SIK pathway: dysregulation in melanomagenesis and regulated use in skin cancer prevention
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The presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage and skin carcinogenesis. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt Inducible Kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CREB regulated transcription coactivator (CRTC) and CRE binding protein (CREB) activity. Here, we describe the development of small molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings are the first to demonstrate a realistic pathway towards UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk. Although MITF normally functions as a regulator of pigmentation, if amplified MITF can serve as a melanoma oncogene shown to cooperate with BRAF (V600E) to induce tumorigenic transformation of melanocytes . Only 10% of melanomas carry an MITF amplification emphasizing the need to identify pathways that modulate MITF expression . Liver kinase B1 (LKB1) regulates many cancer-relevant cell phenotypes and is a known SIK inducer . However, the interaction of the LKB1-SIK pathway and MITF in melanoma formation is not fully understood. Overall 49% of human melanomas in The Cancer Genome Atlas contain aberrations in LKB1, SIK1, SIK2, SIK3, CRTC1, CRTC2, CRTC3, or MITF . Here, we report that the LKB1-SIK axis can negatively regulate MITF expression, and our data suggests this is through increasing CRTC2 cytoplasmic localization. Rescue of LKB1 in LKB1-null G361 melanoma cells suppresses cell proliferation. MAP kinase pathway activation suppresses MITF, and knockdown of all three SIK isoforms rescues MITF expression in NRAS (Q61R) expressing melanocytes. Overall, our findings establish SIK and LKB1 as regulators of the CRTC-CREB-MITF pathway and through this regulation, potentially play a critical role as tumor suppressors in melanoma oncogenesis.