MEK Guards Proteome Stability and Inhibits Tumor-Suppressive Amyloidogenesis via HSF1

Abstract

SUMMARY Signaling through RAS/MAP kinase pathway is central to biology. ERK has long been perceived as the only substrate for MEK. Herein we report that HSF1, the master regulator of the proteotoxic stress response, is a new MEK substrate. Beyond mediating cell-environment interactions, the MEK-HSF1 regulation impacts malignancy. In tumor cells, MEK blockade inactivates HSF1 and thereby provokes proteomic chaos, presented as protein destabilization, aggregation, and, strikingly, amyloidogenesis. Unlike their non-transformed counterparts, tumor cells are particularly susceptible to proteomic perturbation and amyloid induction. Amyloidogenesis is tumor-suppressive, reducing in vivo melanoma growth and contributing to the potent anti-neoplastic effects of proteotoxic stressors. Our findings unveil a key biological function of the oncogenic RAS-MEK signaling in guarding proteostasis and suppressing amyloidogenesis. Thus, proteomic instability is an intrinsic feature of malignant state and, disrupting the fragile tumor proteostasis to promote amyloidogenesis may be a feasible therapeutic strategy.

Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

“…Remarkably, overlapping targets defined by 2/3 pairs of these approaches (NET-seq versus RNA-seq and NET-seq versus ChIP-seq) yielded the same set of HDGs ( (Dai et al, 2007) and the accumulation of toxic protein aggregates (Tang et al, 2015). Surprisingly, HSF1…”

“…(1999). The heat shock response in yeast: differential regulations and Dai, C., Whitesell, L., Rogers, A.B., and Lindquist, S. (2007 Dai, S., Tang, Z., Cao, J., Zhou, W., Li, H., Sampson, S., and Dai, C. (2015). Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK.…”

“…This later observation raises the possibility that Hsf may be further tuned by the activity of distinct stress responses with independent inputs, thus deploying Hsf alongside other evolutionary divergent stress pathways may cause speciation of Hsf regulation. In support of this notion, while the GSR is not conserved in mammals, activity of the mammalian metabolic stress sensor AMPK has recently been shown to have an analogous antagonistic effect on Hsf activation by proteotoxic stress (Dai et al, 2015).…”

“…Analysis of changes in Hsf DNA binding in transformed cells has suggested Hsf's target repertoire is expanded in cancer cells to include many genes not activated during heat shock and with functional roles outside of protein folding (Mendillo et al, 2012). However, it is also that case that Hsf is required to prevent proteostasis collapse in transformed cells (Tang et al, 2015). It has yet to be determined if the additional targets assigned to Hsf in cancer with non-protein folding functions comprise an additional essential role for Hsf besides preventing proteostasis collapse.…”

“…Failure to maintain proteostasis by regulating gene expression has been linked to aging and neurodegenerative diseases , while many cancers are associated with elevated expression of proteostasis factors (Tang et al, 2015). Yeast heat shock factor 1 (Hsf1) was the first eukaryotic proteostasis transcription factor to be discovered (Sorger and Pelham, 1987), which in turn enabled identification of homologous transcription factors across the eukaryotic lineage (Clos et al, 1990;Jakobsen and Pelham, 1991;Rabindran et al, 1991;Scharf et al, 1990).…”