p62/SQSTM1 in liver diseases: the usual suspect with multifarious identities

Abstract

p62/Sequestosome‐1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal pathway. Interestingly, p62 also serves as a signaling scaffold to participate in the regulation of multiple physiological processes, including oxidative stress response, metabolism, inflammation, and programmed cell death. Perturbation of p62 activity has been frequently found to be associated with the pathogenesis of many liver diseases. p62 has been identified as a critical component of protein aggregates in the forms of Mallory–Denk bodies (MDBs) or intracellular hyaline bodies (IHBs), which are known to be frequently detected in biopsy samples from alcoholic steatohepatitis (ASH), non‐alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC) patients. Importantly, abundance of these p62 inclusion bodies is increasingly recognized as a biomarker for NASH and HCC. Although the level of p62 bodies seems to predict the progression and prognosis of these liver diseases, understanding of the underlying mechanisms by which p62 regulates and contributes to the development and progression of these diseases remains incomplete. In this review, we will focus on the function and regulation of p62, and its pathophysiological roles in the liver, by critically reviewing the findings from preclinical models that recapitulate the pathogenesis and manifestation of these liver diseases in humans. In addition, we will also explore the suitability of p62 as a predictive biomarker and a potential therapeutic target for the treatment of liver diseases, including NASH and HCC, as well as recent development of small‐molecule compounds for targeting the p62 signaling axis.

The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications

“…In addition, mice bearing a heterozygous disruption of Beclin1, an essential autophagy gene, exhibit increased susceptibility to spontaneous tumorigenesis in the liver, lung, and lymph tissues [ 109 , 111 ]. A central mechanism in this phenotype is the upregulation of p62/Sequestosome-1 (SQSTM1), an adaptor protein known to regulate NF-κB activation during tumorigenesis [ 112 ]. These principal findings were strengthened further by the loss of function changes observed in autophagy-related genes, in particular a monoallelic deletion of the tumor suppressor gene Beclin1, in multiple tumor types, including HCC [ 113 , 114 ].…”

Bioinformatics-Driven Identification of p62 as A Crucial Oncogene in Liver Cancer

“…Accumulating evidence shows that p62 plays multifaceted roles in LIHC, including its ability to promote LIHC initiation by activating NRF2, mTORC1, and c-MYC pro-oncogenic pathways in hepatocytes (2).…”

“…Nearly three thousand genetic mutations have been identified in LIHC patients, and the most frequently mutated loci include the TERT promoter and the genes coding for P53, b-Catenin, ALB, KEAP1, and NRF2 (2). Interestingly, both Keap1 and NRF2 are the components of the Keap1-NRF2 pathway that transactivate a pool of approximate 250 target genes, of which many are involved in antioxidant defense including p62 (as known as SQSTM1), Cox-2, iNOS, PRDX1, HIF1, NQO1, HMOX1, GSTs, and Keap1 and NRF2 themselves (3)(4)(5)(6).…”

“…As a key transcriptional target of the transcription factor NRF2, p62 plays crucial roles in DNA damage response (DDR), cancer development, mTORC1-mediated nutrient sensing and metabolism, cell death, aging, inflammation and immunity, cell differentiation, osteoclastogenesis, neurotrophin properties and obesity, dependently or independenely of the autophagy machinery (2,(7)(8)(9)(10)(11)(12).…”

“…The tumor-promoting properties of p62 are underscored by the facts that p62 is upregulated in different cancer contexts, including LIHC, and breast and prostate cancers (2,(13)(14)(15)(16)(17), and that p62 is induced by the oncoprotein Ras that accounts for more than 25% of human cancers (18). p62 overexpression in LIHC predicts poor prognosis (15).…”