Post-translational control of cancer cell stress response and metastasis

黑色素瘤是最致命的皮肤癌之一，每年影响成千上万的人。虽然新的靶向和免疫疗法已被批准，但它们通常短暂地起作用，最终产生耐药性，或伴有显著的毒性。黑色素瘤驱动程序组织的转录程序知之甚少。在这里，我们建议解剖黑色素瘤转移支持转录程序组织的转录因子热休克因子1（HSF 1）。虽然这种途径已经进化到帮助细胞适应挑战性条件的存在，但它在癌症中被选择以支持恶性肿瘤。我们的初步数据表明，泛素连接酶FBXW7与HSF 1通过一个保守的由GSK 3 β和ERK 1磷酸化的基序相互作用。FBXW7在黑色素瘤中突变或转录下调，HSF 1核稳定与转移潜能增加和疾病进展相关。我们提出研究黑色素瘤中FBXW7沉默的分子基础（目标1），并通过使用新的体内模型来剖析HSF 1在黑色素瘤发生和发展中的作用以及FBXW7缺失或沉默对HSF 1稳定性的影响（目标2）。此外，我们将确定HSF1调节的转录组，并检查HSF1直接靶点子集的体内效应（目的3）。我们的研究将阐明转移支持转录程序编排的HSF1和它的调节肿瘤抑制因子（FBXW7）经常突变或沉默，并将为我们提供新的治疗黑色素瘤的目标。

Melanoma is one of the deadliest forms of skin cancer and affects tens of thousands of people each year. Although novel targeted and immune therapies have been approved, they often work transiently with resistance eventually ensuing, or are accompanied by significant toxicities. The transcriptional program organized by melanoma drivers is poorly understood. Here we propose to dissect the melanoma metastasis-supportive transcriptional program organized by the transcription factor Heat Shock Factor 1 (HSF1). Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. Our preliminary data indicate that the ubiquitin ligase FBXW7 interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7 is either mutated or transcriptionally down-regulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. We proposed to investigate the molecular basis for FBXW7 silencing in melanoma (Aim 1), and dissect the role of HSF1 in melanoma initiation and progression and the effects of FBXW7 loss or silencing on HSF1 stability by using novel in vivo models (Aim 2). In addition, we will identify the HSF1-regulated transcriptome and examine the in vivo effects of a subset of HSF1 direct targets (Aim 3). Our studies will elucidate the metastasis-supportive transcriptional program orchestrated by HSF1 and its regulation by a tumor suppressor (FBXW7) frequently mutated or silenced and will provide us with novel therapeutic targets for melanoma.