MORC protein family-related signature within human disease and cancer

Abstract

The microrchidia (MORC) family of proteins is a highly conserved nuclear protein superfamily, whose members contain common domain structures (GHKL-ATPase, CW-type zinc finger and coiled-coil domain) yet exhibit diverse biological functions. Despite the advancing research in previous decades, much of which focuses on their role as epigenetic regulators and in chromatin remodeling, relatively little is known about the role of MORCs in tumorigenesis and pathogenesis. MORCs were first identified as epigenetic regulators and chromatin remodelers in germ cell development. Currently, MORCs are regarded as disease genes that are involved in various human disorders and oncogenes in cancer progression and are expected to be the important biomarkers for diagnosis and treatment. A new paradigm of expanded MORC family function has raised questions regarding the regulation of MORCs and their biological role at the subcellular level. Here, we systematically review the progress of researching MORC members with respect to their domain architectures, diverse biological functions, and distribution characteristics and discuss the emerging roles of the aberrant expression or mutation of MORC family members in human disorders and cancer development. Furthermore, the illustration of related mechanisms of the MORC family has made MORCs promising targets for developing diagnostic tools and therapeutic treatments for human diseases, including cancers.

Fig. 1. The arrangement of the domains of human MORC family.

According to given evidence and Pfam analysis results, the domain structures in human MORC protein have been defined with three hallmarks: a conserved GHKL-ATPase domain at N-terminal, a conserved CW-type zinc finger domain in the middle and several coiled-coil domains. In addition, MORC proteins in eukaryotes contain a structure similar to that of the second domain of ribosomal S5 proteins (hence named the MORC-S5 domain). Aside from these common structural determinants, human MORCs also exhibit unique structural motifs, such as nuclear matrix binding and RNA bindings, which are particularly apparent in MORC3.

Fig. 2. MORC family expression in normal human tissues.

A mRNA expression of MORC family in normal tissues from GTEx; B protein expression in normal tissues and cell lines from Proteomics DB (https://www.genecards.org).

Fig. 3. The mRNA expression of MORC family in various cancer types.

The CCLE database (https://portals.broadinstitute.org/ccle/home) demonstrated the diversified expression level of MORC1 (A), MORC2 (B), MORC3 (C), and MORC4 (D) with RNA sequence databases in different cancer cell lines. MORC1 to MORC4 expressed the high level in myeloma, leukemia, breast, gastrointestinal, liver and kidney cancer cell lines. All the values of mRNA expression (RNAseq) were processed by log2-fold-change. A box plot is sorted and colored by average distribution of a gene’s expression in a lineage. Lineages are composed of a number of cell lines from the same area or system of the body. The highest average distribution is on the left and is colored red. The dashed line within a box is the mean.

Fig. 4. The relationship of MORC family and cancers.

In regulation of DNA damage response and gene transcription, MORC family regulate the expression of key proteins by interacting with their promoters (e.g. CAIX, NDRG1, NF2, KIBRA, and MID2) or their stability/activity by direct interaction (e.g. CTNND1, C/EBPα) in pathways associated with cancer development, regulating cell proliferation, migration, invasion and metastasis of cancers, moreover affecting chemoresistance and stemness of cancers. Meanwhile, the stabilization/activity of MORC family are regulated by chromatin-associated enzymes (e.g. NAT10) and hormone (e.g. estrogen) in specific cancer, such as MORC2 in breast cancer. Furthermore, the oncogenic mutation of MORC family involves the progression of breast cancer, such as MORC1 and MORC2 M276I.

Fig. 5. An overview of the types of MORC family mutation observed.

According to the Cosmic public databases (https://cancer.sanger.ac.uk/cosmic), these charts show a summary of the types of mutation that have been observed in samples for MORCs gene. These tables show the number of samples recorded as having a particular type of mutation, with the number in brackets giving the percentage of samples with that type of mutation. Meanwhile, note that a sample may have more than one type of mutation, so the total number of samples determined by simply summing the values in the table may not match the total number of unique samples given under the table. For the same reason, summing the percentages in the table may give a value of greater than 100%.