The MAL Family of Proteins: Normal Function, Expression in Cancer, and Potential Use as Cancer Biomarkers

Abstract

The MAL family of integral membrane proteins consists of MAL, MAL2, MALL, PLLP, CMTM8, MYADM, and MYADML2. The best characterized members are elements of the machinery that controls specialized pathways of membrane traffic and cell signaling. This review aims to help answer the following questions about the MAL-family genes: (i) is their expression regulated in cancer and, if so, how? (ii) What role do they play in cancer? (iii) Might they have biomedical applications? Analysis of large-scale gene expression datasets indicated altered levels of MAL-family transcripts in specific cancer types. A comprehensive literature search provides evidence of MAL-family gene dysregulation and protein function repurposing in cancer. For MAL, and probably for other genes of the family, dysregulation is primarily a consequence of gene methylation, although copy number alterations also contribute to varying degrees. The scrutiny of the two sources of information, datasets and published studies, reveals potential prognostic applications of MAL-family members as cancer biomarkers—for instance, MAL2 in breast cancer, MAL2 and MALL in pancreatic cancer, and MAL and MYADM in lung cancer—and other biomedical uses. The availability of validated antibodies to some MAL-family proteins sanctions their use as cancer biomarkers in routine clinical practice.

MAL expression downregulation through suppressive H3K27me3 marks at the promoter in HPV16-related cervical cancers is prognostically relevant and manifested by the interplay of novel MAL antisense long noncoding RNA AC103563.8, E7 oncoprotein and EZH2

“…This pair was one out of 17 such gene pairs, which further revealed increased correlative strength among the patients, as compared to the normal individuals. Thus, along with the availability of reports highlighting MAL downregulation, concomitant with MAL promoter hypermethylation as a biomarker of CaCx [ 22 , 28 ], we proceeded to further unfold the biological and clinical relevance of MAL downregulation in HPV16-positive CaCx patients.…”

“…Therefore, we selected this gene pair (MAL and its antisense AC103563.8) out of several such gene pairs identified through our RNA seq analysis [ 19 ]. We were guided by the fact that MAL expression downregulation in various cancers has established MAL as a potent biomarker for cancer development in association with methylation of MAL promoter [ 22 ]. Clearly, we recorded that MAL gene expression downregulation was significantly associated with poor patient overall survival in our study, and also validated this observation in the TCGA CESC dataset.…”

“…This gene pair was highly downregulated and showed significantly enhanced correlation within HPV16-positive CaCx cases, in comparison to healthy individuals, as identified employing ss-RNA seq in our previous study [ 19 ]. MAL is a known biomarker for CaCx [ 20 – 22 ]. It is also known that hypermethylation of MAL promoter increases with disease severity [ 23 ].…”

“…The combination of HPV testing along with these methylation markers are useful as an effective molecular screening strategy for HPV-positive patients. Therefore, based on the relevance of MAL in CaCx pathogenesis [ 22 , 29 ], we undertook further analyses to uncover the interplay between HPV16 E7 oncoprotein, host molecules MAL, AC103563.8 and EZH2, a PRC2 complex member, which is known to create chromatin suppression marks and also facilitate promoter hypermethylation [ 30 ]. Our findings strongly justify the biological relevance of correlated co-expression of antisense lncRNAs, with the sense genes and the potential role of the AC103563.8/E7/EZH2 axis in MAL deregulated expression, unveiling a novel path for exploring therapeutics of HPV16-related CaCx.…”

MYADM binds human parechovirus 1 and is essential for viral entry

“…Here, we use genome-scale CRISPR/Cas9 screening in human cells and identify myeloid-associated differentiation marker (MYADM) as an essential host factor for PeV-A1, PeV-A2 and PeV-A3 infection. MYADM is a broadly expressed plasma membrane protein that partitions in detergent-resistant membranes suggesting its association with membrane rafts 13 , 14 . We show that MYADM is required for viral entry in cell lines and confirm that MYADM mediates infection in human gastrointestinal epithelial organoids representing a primary site of PeV-A infection 7 , 8 .…”