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，但它们往往是短暂的，最终会产生耐药性，或者伴随着显著的毒性。由黑色素瘤驱动因子组织的转录程序尚不清楚。在这里，我们建议剖析由转录因子热休克因子1 （HSF1）组织的支持黑色素瘤转移的转录程序。尽管这一途径已经进化为帮助细胞适应具有挑战性的条件，但它在癌症中被用来支持恶性肿瘤。我们的初步数据表明，泛素连接酶FBXW7通过一个被GSK3β和ERK1磷酸化的保守基序与HSF1相互作用。FBXW7在黑色素瘤和HSF1核稳定中发生突变或转录下调，与转移潜力增加和疾病进展相关。我们提出研究FBXW7在黑色素瘤中沉默的分子基础（Aim 1），并通过新的体内模型分析HSF1在黑色素瘤发生和进展中的作用，以及FBXW7缺失或沉默对HSF1稳定性的影响（Aim 2）。此外，我们将确定HSF1调控的转录组，并检查HSF1直接靶点子集的体内效应（目的3）。我们的研究将阐明由HSF1介导的支持转移的转录程序，以及由一个经常突变或沉默的肿瘤抑制因子（FBXW7）调控的转录程序，并将为我们提供新的黑色素瘤治疗靶点。

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.