Cancer: From Wild-Type to Mutant Huntingtin

Abstract

Huntingtin (HTT) is a scaffold protein mostly known because it gives rise to the severe and incurable inherited neurological disorder Huntington’s disease (HD) when mutated. The Huntingtin gene (HTT) carries a polymorphic trinucleotide expansion of CAGs in exon 1 that ranges from 9 to 35 in the non-HD affected population. However, if it exceeds 35 CAG repeats, the altered protein is referred to as mutant HTT and leads to the development of HD. Given the wide spectrum of severe symptoms developed by HD individuals, wild-type and mutant HTT have been mostly studied in the context of this disorder. However, HTT expression is ubiquitous and several peripheral symptoms in HD have been described, suggesting that HTT is of importance, not only in the central nervous system (CNS), but also in peripheral organs. Accordingly, HTT and mutant HTT may interfere with non-brain-related diseases. Correlative studies have highlighted a decreased cancer incidence in the HD population and both wild-type and mutant HTT have been implicated in tumor progression. In this review, we describe the current evidence linking wild-type and mutant HTT to cancer and discuss how CAG polymorphism, HTT function, and partners may influence carcinogenesis and metastatic progression.

miR-146a Overexpression in Oral Squamous Cell Carcinoma Potentiates Cancer Cell Migration and Invasion Possibly via Targeting HTT

“…Our results suggest HTT as a possible diagnostic or therapeutic target in OSCC. Thion and colleagues had reported the anti-metastatic role of the HTT gene in breast cancer (23,38). We unraveled the strong association between the lower expression of HTT in OSCC/HNSCC with reduced survival rate/duration and vice versa, indicating a critical role of HTT in OSCC.…”

Analysis of the Circadian Regulation of Cancer Hallmarks by a Cross-Platform Study of Colorectal Cancer Time-Series Data Reveals an Association with Genes Involved in Huntington’s Disease

“…HTT is expressed throughout the body and the mutant protein not only affects the brain but also peripheral tissues as weight loss, cardiomyopathies and skeletal muscle malfunction have been described for HD [59]. Interestingly, cancer has been reported to account only for 5% of the leading causes for death in HD [45].…”

“…However, mutant HTT can also contribute to the severity and progression of a specific cancer type. For example, while HTT regulates the normal development of the mammary tissue [59,60], mutant HTT expression is pro-metastatic in breast cancer and can accelerate tumor development through ErbB2/HER2 signaling [61]. Notably, mHTT has been reported to interact directly with SIRT1, a clock gene, and inhibit its activity [62].…”

Prion-like mechanisms in neurodegenerative disease: Implications for Huntington’s disease therapy

“…The presence of mHTT also interferes with protein synthesis and quality control (proteostasis) leading to impaired cellular function and loss of viability. There is currently no cure or effective treatment for HD …”