Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Abstract

Cancer genomes maintain a complex array of somatic alterations required for maintenance and progression of the disease, posing a challenge to identify driver genes among this genetic disorder. Toward this end, we mapped regions of recurrent amplification in a large collection (n ¼ 392) of primary human cancers and selected 620 genes whose expression is elevated in tumors. An RNAi loss-of-function screen targeting these genes across a panel of 32 cancer cell lines identified potential driver genes. Subsequent functional assays identified SHMT2, a key enzyme in the serine/glycine synthesis pathway, as necessary for tumor cell survival but insufficient for transformation. The 26S proteasomal subunit, PSMB4, was identified as the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo. Elevated expression of SHMT2 and PSMB4 was found to be associated with poor prognosis in human cancer, supporting the development of molecular therapies targeting these genes or components of their pathways. Cancer Res; 74(11); 3114-26. Ó2014 AACR.

Integrated Omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact

“…This upregulation at the protein level, along with that of SHMT2, is consistent with their elevated mRNA expression in various cancer types 45 . SHMT2 was implicated as a driver required for survival in a series of cancer cell lines 46 , and was shown to be upregulated and required for maintenance of redox balance and tumour cell survival in response to hypoxia 47 . Finally, in apparent contrast to its metabolism function in mitochondria, SHMT2 was recently identified as an adaptor subunit of a cytosolic BRISC (BRCC36 isopeptidase complex) deubiquitinase 48 .…”

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

“…These include DHFR (dihydrofolate reductase), an enzyme strongly inhibited by current antifolates, and TYMS (thymidylate synthase), the target of the important chemotherapeutic 5-fluorouracil (Huennekens, 1994;Longley et al, 2003). Equally upregulated are two genes of mitochondrial 1C transformations: SHMT2 (mitochondrial serine hydroxymethyl transferase) and MTHFD2 (mitochondrial methylenetetrahydrofolate dehydrogenase) (Jain et al, 2012;Lee et al, 2014;Nilsson et al, 2014). Together these enzymes, both of which lie in a pathway essential for embryonic development (Di Pietro et al, 2002;Momb et al, 2013), transform serine into glycine and a formyl unit attached to THF (Figure 1a).…”

Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

“…A recent metastudy including microarray data from more than 1,900 tumor tissues of 19 different cancer types suggested that the mitochondrial 1-carbon metabolism is the most deregulated metabolic pathway in human cancers (20). Intriguingly, SHMT2 and MTHFD2 were found to be overexpressed in multiple human cancers and were correlated with shorter survival in breast cancer patients (16,20,21). Knockdown of MTHFD2 in breast cancer cells suppressed proliferation and induced apoptosis (20).…”