WWP1 targeting MUC1 for ubiquitin-mediated lysosomal degradation to suppress carcinogenesis

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers. Show more

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a multifunction protein containing an N-terminal C2 domain, four tandem WW domains for substrate binding, and a C-terminal catalytic HECT domain for ubiquitin transferring. WWP1 has been suggested to function as the E3 ligase for several PY motif-containing proteins, such as Smad2, KLF5, p63, ErbB4/HER4, RUNX2, JunB, RNF11, SPG20, and Gag, as well as several non-PY motif containing proteins, such as TβR1, Smad4, KLF2, and EPS15. WWP1 regulates a variety of cellular biological processes including protein trafficking and degradation, signaling, transcription, and viral budding. WWP1 has been implicated in several diseases, such as cancers, infectious diseases, neurological diseases, and aging. In this review article, we extensively summarize the current knowledge of WWP1 with special emphasis on the roles and action of mechanism of WWP1 in signaling and human diseases. Show more

Cells are thought to adapt to proteasome inhibition by using alternative pathways for degradation such as autophagy. Sha et al. now report that cells rapidly induce GABARAPL1 and p62 upon proteasome inhibition, but this promotes cell survival by sequestering ubiquitinated and sumoylated proteins long before the cells induce other Atg genes and activate autophagy. Show more