Hsp90 in Cancer: Transcriptional Roles in the Nucleus

Abstract

Hsp90 plays a key role in fostering metabolic pathways essential in tumorigenesis through its functions as a molecular chaperone. Multiple oncogenic factors in the membrane and cytoplasm are thus protected from degradation and destruction. Here, we have considered Hsp90's role in transcription in the nucleus. Hsp90 functions both in regulating the activity of sequence-specific transcription factors such as nuclear receptors and HSF1, as well as impacting more globally acting factors that act on chromatin and RNA polymerase II. Hsp90 influences transcription by modulating histone modification mediated by its clients SMYD3 and trithorax/MLL, as well as by regulating the processivity of RNA polymerase II through negative elongation factor. It is not currently clear how the transcriptional role of Hsp90 may be influenced by the cancer milieu although recently discovered posttranslational modification of the chaperone may be involved. Dysregulation of Hsp90 may thus influence malignant processes both by modulating the function of specific transcription factors and effects on more globally acting general components of the transcriptional machinery.

Keywords: Cancer transcription; Hsp90; Modification; Posttranslational; RNA polymerase II; Trithorax.

Figure 1. Hsp90 Interaction with HSF1 and HSP Synthesis in Stress and Cancer.

HSF1 is depicted as being regulated by Hsp90 in a negative feedback loop. Escape from Hsp90 repression may involve modifications to HSF1 and Hsp90 itself and may include effects on the transcription factor or on more global factors including promoter proximal pausing and histone modifications.

Figure 2. Participation of Hsp90 in Transcription.

Upper part of figure depicts Hsp90 associated with a transcription factor (TF) in a chaperone-co-chaperone complex (p23, immunophilin (IF) complex -TPR protein Hop and Hsp70 and Hsp40). This type of regulation is found in nuclear receptors and HSF1. In the lower part of the figure, we show Hsp90 participating in global effects on transcriptional activation mediated by SMYD3, Trx/MLL, Rvb and NELF involving chromatin remodeling, histone modification and Pol II regulation.

Figure 3. Posttranscriptional Modifications that may Influence Role of Hsp90 in Transcription.

We depict Hsp90 phosphorylation by CK2, DNA-PK and Src as well as its SUMOylation as known PTMs that may modulate its impact on transcriptional events.