Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer

Abstract

In order to cope with increased demands for energy and metabolites as well as to enhance stress resilience, tumor cells develop various metabolic adaptations, representing a hallmark of cancer. In this regard, the dysregulation of sulfur metabolism that may result in elevated levels of volatile sulfur compounds (VSCs) in body fluids, breath, and/or excretions of cancer patients has recently gained attention. Besides hydrogen sulfide (H₂S), methanethiol is the predominant cancer-associated VSC and has been proposed as a promising biomarker for non-invasive cancer diagnosis. Gut bacteria are the major exogenous source of exposure to this foul-smelling toxic gas, with methanethiol-producing strains such as Fusobacterium nucleatum highly abundant in the gut microbiome of colorectal carcinoma (CRC) patients. Physiologically, methanethiol becomes rapidly degraded through the methanethiol oxidase (MTO) activity of selenium-binding protein 1 (SELENBP1). However, SELENBP1, which is considered a tumor suppressor, is often downregulated in tumor tissues, and this has been epidemiologically linked to poor clinical outcomes. In addition to impaired removal, an increase in methanethiol levels may derive from non-enzymatic reactions, such as a Maillard reaction between glucose and methionine, two metabolites enriched in cancer cells. High methionine concentrations in cancer cells may also result in enzymatic methanethiol production in mitochondria. Moreover, enzymatic endogenous methanethiol production may occur through methyltransferase-like protein 7B (METTL7B), which is present at elevated levels in some cancers, including CRC and hepatocellular carcinoma (HCC). In conclusion, methanethiol contributes to the scent of cancer as part of the cancer-associated signature combination of volatile organic compounds (VOCs) that are increasingly being exploited for non-invasive early cancer diagnosis.

Keywords: CRC; H2S; MTO; SELENBP1; VSC; methyl mercaptan; microbiota; tumor.

Figure 1

Alternate metabolic fates of methanethiol. (A) Physiologically, degradation of methanethiol occurs predominantly through SELENBP1, which acts as MTO, catalyzing the rapid oxidative conversion of methanethiol to H₂S, H₂O₂, and formaldehyde. (B) In SELENBP1-deficient cancer cells and in cells that possess an inactive MTO due to mutations (SNPs) in the SELENBP1 gene, methanethiol is methylated to DMS, which can be oxidized subsequently to DMSO and DMSO₂. Methanethiol and DMS may be detected in the exhaled breath of afflicted persons. Scheme created with Biorender.com.

Figure 2

SELENBP1 as a tumor suppressor. SELENBP1 has been reported to inhibit cell proliferation, angiogenesis, metastasis, and resistance to chemotherapy as well as to promote apoptotic cell death. Scheme created with Biorender.com.

Figure 3

Dysregulation of sulfur metabolism in cancer cells may result in elevated levels of methanethiol and its derivatives in body fluids and excreted gases of cancer patients. (A) In healthy persons, the vast majority of methanethiol derives from the metabolic activity of gut bacteria. Some methanethiol may diffuse into the colonic epithelium, where it is rapidly oxidized by SELENBP1. (B) In cancer patients, endogenous synthesis of methanethiol may substantially increase due to elevated levels of metabolites, such as methionine (Met), glucose (Glc), H₂S, and SAM, in tumor cells. Downregulation of SELENBP1 and upregulation of METTL7B may result in a shift from oxidation to methylation of methanethiol. As methanethiol and its methylated derivatives are highly volatile, they may be used as biomarkers for non-invasive cancer detection. Adducts of methanethiol with proteins may also be detected, as it has been demonstrated for human serum albumin (HSA). Scheme created with Biorender.com.