Abstract
The SKP1, CUL1, F-box protein (SCF) complex represents a family of 69 E3 ubiquitin ligases that poly-ubiquitinate protein substrates marking them for proteolytic degradation via the 26S proteasome. Established SCF complex targets include transcription factors, oncoproteins and tumor suppressors that modulate cell cycle activity and mitotic fidelity. Accordingly, genetic and epigenetic alterations involving SCF complex member genes are expected to adversely impact target regulation and contribute to disease etiology. To gain novel insight into cancer pathogenesis, we determined the prevalence of genetic and epigenetic alterations in six prototypic SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) from patient datasets extracted from The Cancer Genome Atlas (TCGA). Collectively, ~45% of observed SCF complex member mutations are predicted to impact complex structure and/or function in 10 solid tumor types. In addition, the distribution of encoded alterations suggest SCF complex members may exhibit either tumor suppressor or oncogenic mutational profiles in a cancer type dependent manner. Further bioinformatic analyses reveal the potential functional implications of encoded alterations arising from missense mutations by examining predicted deleterious mutations with available crystal structures. The SCF complex also exhibits frequent copy number alterations in a variety of cancer types that generally correspond with mRNA expression levels. Finally, we note that SCF complex member genes are differentially methylated across cancer types, which may effectively phenocopy gene copy number alterations. Collectively, these data show that SCF complex member genes are frequently altered at the genetic and epigenetic levels in many cancer types, which will adversely impact the normal targeting and timely destruction of protein substrates, which may contribute to the development and progression of an extensive array of cancer types.
Highlights
In 2020, ~20 million individuals throughout the world were newly diagnosed with cancer, while ~10 million succumbed to the disease [1]
We discovered that CNAs occur frequently for all six genes and that while CUL1 and SKP2 predominantly exhibit copy number gains, the remaining genes (SKP1, RBX1, FBXW7 and FBXO5) exhibit more copy number losses that correspond with reduced mRNA expression
To determine the mutational frequency and types of alterations occurring in the six prototypic and representative SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) across various cancers, The Cancer Genome Atlas (TCGA) data [35,36,37] were assessed as detailed in Materials and Methods
Summary
In 2020, ~20 million individuals throughout the world were newly diagnosed with cancer, while ~10 million succumbed to the disease [1] Despite these statistics, the molecular determinants (i.e., aberrant genes, proteins and pathways) underlying cancer development and progression remain poorly understood. Decades of biochemical and genetic data have shown that aberrant expression/abundance of key proteins involved in critical biological processes (e.g., cell cycle regulation, DNA damage repair, and apoptosis [2,3,4,5,6,7,8]) are drivers of disease development and progression [9,10,11,12]. Additional studies are required to understand its role in disease pathogenesis as the molecular mechanisms underlying aberrant SCF complex function remain largely unknown
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