Oncogenes and tumor suppressor genes: functions and roles in cancers

Abstract

Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X-linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X-linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X-linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X-linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X-linked TSGs in sex chromosome-autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X-linked TSG in immunomodulation and in gender-based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X-linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.

Keywords: X chromosome–autosome crosstalk; X‐chromosome inactivation; cancer signaling; cancer therapy; ncRNAs; tumor suppressor genes (TSGs).

FIGURE 1

X‐chromosome inactivation and their involvement in cancers: (A) Single‐hit hypothesis (left upper panel) and Knudson's two‐hit hypothesis (left lower panel) and (B) X chromosome showing position of TSGs mainly on its q‐arm (right panel).

FIGURE 2

Cell signaling circuitry related to X‐linked tumor suppressor genes. TSGs encoding variety of proteins that help to regulate cellular growth are described. Genes playing a role in the control of cell surface receptors for cytokines, growth factors, signal transduction molecules, and transcription factors, epigenetic regulators, regulators of the cell cycle, and regulators of apoptosis in different cancers are shown.

FIGURE 3

STRING‐based gene interaction maps and network circuitry. Tumor suppressor genes, including X‐linked tumor suppressor genes having molecular interactions with other target genes or proteins through physical and functional associations are shown.

FIGURE 4

A heatmap representation of the coexpression scores of X‐linked TSGs based on RNA expression patterns and on protein c‐regulation provided by ProteomeHD.

FIGURE 5

A comprehensive figure depicts the epigenetic silencing of tumor suppressor genes through various alterations including DNA methylation, nucleosome remodeling, and histone alterations. The CpG island in the promoter region methylates and induces the normal cell to metastasis contributing in the development of cancer cells by inactivating the tumor suppressor gene transcription.

FIGURE 6

The schematic representation summarizes different approaches to target lncRNAs in the cytoplasm and nucleus. (A) Transcriptional inhibition can be attained by CRISPR/Cas9 to delete regions of interest in the loci of lncRNA. (B) Transcriptional upregulation of tumor suppressors can be attained by knocking down of the corresponding natural antisense transcripts (NATs). (C) Antisense oligonucleotides (ASOs) can posttranscriptionally knock down lncRNAs that are overexpressed in cancers. (D) Posttranscriptional silencing can be attained by siRNAs targeting lncRNAs. siRNAs stimulate dicer activity and recruit the RISC complex (RNA‐induced silencing complex) to posttranscriptionally degrade target RNAs. (E) Steric inhibition of lncRNA–protein interactions can be achieved using small molecules, or modified ASOs that cannot stimulate an RNA degradation pathway.

FIGURE 7

Functional implications of tumorigenic miRNAs (onco‐miRs) and antitumor miRNAs.

FIGURE 8

KEGG pathway—onco‐microRNAs in cancer (hsa05206) displaying TSGs in Homo sapiens in different cancers: (A) breast (left panel) and (B) colorectal cancer (right upper panel) and glioma (right lower panel) showing targeted pathways.