More Than Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Diseases

Abstract

Cells encounter a myriad of endogenous and exogenous stresses that could perturb cellular physiological processes. Therefore, cells are equipped with several adaptive and stress-response machinery to overcome and survive these insults. One such machinery is the heat shock response (HSR) program that is governed by the heat shock factors (HSFs) family in response towards elevated temperature, free radicals, oxidants, and heavy metals. HSF4 is a member of this HSFs family that could exist in two predominant isoforms, either the transcriptional repressor HSFa or transcriptional activator HSF4b. HSF4 is constitutively active due to the lack of oligomerization negative regulator domain. HSF4 has been demonstrated to play roles in several physiological processes and not only limited to regulating the classical heat shock- or stress-responsive transcriptional programs. In this review, we will revisit and delineate the recent updates on HSF4 molecular properties. We also comprehensively discuss the roles of HSF4 in health and diseases, particularly in lens cell development, cataract formation, and cancer pathogenesis. Finally, we will posit the potential direction of HSF4 future research that could enhance our knowledge on HSF4 molecular networks as well as physiological and pathophysiological functions.

Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology

“…Dysregulation of HSF4 expression might induce carcinogenesis. HSF4 was found to be upregulated in HCC tissues and, more important, elevated in primary HCC tissues derived from recurrent patients; consequently, HSF4 was considered an independent poor-prognosis predictor after resection [67,68]. Our analysis identified HSF4 as being upregulated only in the HCV tumor group.…”

Expression patterns and prognostic value of key regulators associated with m7G RNA modification based on all gene expression in colon adenocarcinoma

“…HSF4 has various physiological functions as follows: regulating the transcriptional program of the heat response or stress response; regulating cell proliferation and differentiation during development; regulating DNA damage repair, and regulating normal physiological processes. HSF4’s Alterations are also strongly linked to cataracts, cancer, and other illnesses [ 21 ]. Mice lacking HSF4 produce irregular lenses and develop cataracts early in experiments [ 22 – 24 ].…”

Transcriptomic profiles of the ruminal wall in Italian Mediterranean dairy buffaloes fed green forage

“…Particularly notable was up-regulation of genes whose products counteract stressful conditions, such as NUDT18 , DNAJA4 and HSF4 genes. NUDT18 catalyzes the hydrolysis of 8-oxo-dGTP - one of the best characterized DNA damages caused by oxidative stress - to produce the monophosphate form 8-oxo-dGMP (odGMP), which is unusable for DNA synthesis, thus preserving cells from oxidation-mediated mutations [ 63 ]; DNAJA4 belongs to the family of heat shock proteins HSP40, which cooperate with HSP70 chaperones to counteract protein misfolding and aggregation in stress conditions [ 64 ]; HSF4 gene encodes a factor that modulates the expression of heat shock proteins under stressful conditions [ 65 ] and exerts a protective effect against oxidative stress [ 66 ]. These findings suggest that green feed may exert an anti-oxidant function, by positively modulating factors that counteract stressful stimuli.…”